The Effect of Parkinson's Disease - Research Paper Example

? Effects of Parkinson’s disease Parkinson’s disease is caused by the degeneration of dopaminergic neurons in the substantianigra of the brain and is characterized by various motor and non-motor symptoms. The history of this disease can be traced back to 1817 and since then different discoveries have been made to improve its treatment and understanding of pathogenesis. The etiology of the disease has been discussed in relation to both the genetic and environmental factors. Important genes causing inherited Parkinson’s disease are LRRK2, PINK1, Parkin gene, SNCA and DJ-1. The mutations can result either in dominant or recessive Parkinson’s disease. Environmental factors playing an important role are pesticides, industrial fumes and nicotine. The symptoms of the Parkinson’s disease can either be motor or non-motor. The major motor symptoms are tremors, bradykinesia, rigidity and postural abnormalities. The non-motor symptoms can either be cognitive abnormalities, sleep disorders or autonomic failure. Treatment strategies include controlling the symptoms. The preferred drug choices include levodopa/carbidopa, dopamine agonists, COMT inhibitors and non-dopaminergic drugs. Surgical methods are also being tested for treatment. The Effects of Parkinson’s disease Parkinson’s disease is a neurodegenerative disorder which usually manifests after the age of 50. With its discovery in 1817 by James Parkinson, much advancement has been made in the clinical features and treatment strategies of this disease. Parkinson’s disease is a pathological condition that comprises of motor deformities like rest tremors, postural deformities, slowness in movements and rigidity caused by the inactivity of the dopaminergic neurons in the substantia nigra of the brain. Initially it was thought to be only caused by environmental factors or unknown reasons, but now many genes have been discovered that cause dominant and recessive inheritance of this disease. Lewy bodies are the major finding in such patients which are inclusions of protein aggregates. The effects of Parkinson’s disease are widespread and include both the motor and non-motor systems of the body (Jankovic 2007; Burbulla & Kruger 2011). James Parkinson was the first scientist who brought forward neurological disease “shaking palsy” in his published document “An essay On Shaking Palsy” in 1817. Jean-Martin Charcot named this disease Parkinson’s disease in 1872 and also made further new investigations in the etiology and clinical presentation. He described two different presentations; one with tremors and the other without tremors. Therefore he stated that patients of Parkinson’s disease are not necessarily weak and also brought in light the pain, dysautonomia and joint anomalies that might be associated with Parkinson’s disease. Another important input by Charcot was proper classification of Parkinson’s disease and differentiating it from other neurological disorders that were also associated with tremors. The male preponderance of Parkinson disease was first highlighted by Gowers in 1888 after examining 80 patients. It was in 1919 that the basic morphological feature of Parkinson disease was discovered as the loss of cells in substantia nigra. In 1960, the recognition of decreased dopamine levels in the PD patients’ striatum by Ehringer and Hornykiewicz was a breakthrough in the treatment therapies for Parkinson disease. Surgical treatments involving excision of cerebral cortex to improve tremors were first proposed by Bucy and Case in 1939.Other therapies like massage techniques, exercise have also surfaced but they are yet to be scientifically proven (Goetz 2011; Jankovic 2007). The genetic and environmental factors play an important role in the protein aggregation and mitochondrial dysfunction that is considered as the basic pathological mechanism causing Parkinson’s disease. Alpha-synuclein (SNCA) gene that undergoes mutations has been established as a major cause of familial Parkinsonism. These mutations lead to a loss of dopaminergic neurons by causing pathological aggregation of alpha-synuclein protein. Carriers of these mutations have shown a 100% result of Lewy bodies’ formation containing alpha-synuclein aggregates. Three types of missense mutations have been discovered which are A53T, A30P and E64K. Another gene causing familial Parkinson disease is PARK2 gene which encodes the Parkin, anubiquitin E3 ligase. Mutations in the PARK2 gene lead to an abnormal degradation of proteins and ultimately pathological aggregation of proteins in Parkinson patients. LRRK2 gene loss has been observed in aged mice which show alpha-synuclein aggregation and neurodegenerative loss. Apart from genetic factors, environmental agents have also been recognized that cause impairment of protein degradation and accumulation of proteins with the passage of time. These cause inhibition of proteasomal components of degradation pathway. These inhibitors can either be naturally occurring or synthetic. Some of the environmental toxins recognized are components of pesticides, industrial fumes and manganese, found specifically in welding fumes and nicotine, hydroquinone found in cigarette smoke. A group of genes are responsible for causing autosomal recessive Parkinson disease. Because of mutations in Parkin gene, PINK1 gene and DJ-1 gene, there is a degradation of mitochondrial proteins and consequently brain cell death. Impaired mitochondrial proteins and defected macro-autophagy result in a dysfunctional cell death process and accumulation of abnormal proteins, respectively. Environmental factors can also lead to neurotoxicity causing mitochondrial dysfunction. MPTP and rotenone leads to failure of mitochondrial complex 1 and subsequently protein aggregation and destruction of DNA and lipids in the affected part of brain (Burbulla & Kruger 2011). The clinical features of Parkinson’s disease can be grouped into motor and non-motor features. The motor features include tremors, bradykinesia (slowness of movements), rigidity and postural instability. The tremors in PD are characteristically rest tremors and are mostly seen in the distal extremities. Apart from rest tremors, postural tremors can also be presented. Rigidity affects the neck, hips, shoulders, wrists and ankles. There is increased resistance to movements and this is accompanied with pain. Parkinson patients also present with other motor dysfunctions like slow daily activities, shuffling gait, difficulty in changing position on chair or bed. Patients also suffer from speech abnormalities and are characterized by a soft breathy tone. Their speech is given a specific name of “tip-of-tongue speech”. Ophthalmological manifestations can also be seen which include blepherospasm, hallucinations, irritability in eyes and limited upward gaze. The orofacial-lrayngeal bradykinesia presents with dysarthria (difficulty in speech), hypophonia and dysphagia (difficulty in swallowing). Restrictive or obstructive lung diseases can lead to mortality in Parkinson’s disease patients. Pneumonia, restricted neck movements and cervical arthrosis are the respiratory manifestations in PD patients. Non-motor symptoms are observed when other parts of the brain for instance noradrenergic, cholinergic and serotonin areas of the brain undergo degeneration. These features are further classified into autonomic dysfunction, cognitive abnormalities, and sensory defects and sleep disorders. Autonomic impairment leads to orthostatic hypotension, erectile abnormities and abnormalities in sphincter regulation. Dementia associated with PD is seen in majority of patients. Other neuropsychiatric abnormalities like depression, anxiety, hallucinations have also been reported by most of the patients of Parkinson’s disease. Patients also complain of increase in libido, obsessive-compulsive habits for food or certain activities. The sleep disorders include increased daytime sleep, dramatic dreams, and restless leg syndrome and are considered to be caused by the loss of orexin neurons in Parkinson’s patients. Patients also present with sensory features of oral and genital pain, paresthesia and hyposmia (reduced sensation of smell) (Jankovic 2007). Before starting treatment of Parkinson’s disease, the level of abnormalities both motor and non-motor should be assessed and confirmed by the doctor. Moreover, the drugs are only effective in controlling the intensity of symptoms or controlling them. The initial drugs of choice are levodopa/carbidopa and dopamine agonists. Bradykinesia is controlled very effectively by Levodopa therapy along with carbidopa, which improves the effects of levodopa. Levodopa induced dyskinesia can be reduced by controlling the dosage of drug, through other drugs (Amantadine, Propranolol) to improve this symptom and by surgical measures. Continuous dopaminergic stimulation is a method to avoid the motor fluctuations caused by the prolonged usage of levodopa. These include intramuscular or intravenous administration of levodopa ethyl ester, oral solutions of levodopa and subcutaneous administration. COMT inhibitors which include Entacapone inhibit the COMT and are given with levodopa. They increase the absorption of levodopa and are associated with least adverse effects other than nausea and enhanced dyskinesia. Dopamine agonists include bromocriptine, pramipexole and ropinirole. They directly affect the dopaminergic receptors in Parkinson’s disease patients. The monoamine oxidase-type B inhibitors which include selegiline and rasagiline are considered neuroprotective along with dopamine agonists. Symptomatic treatment can be achieved by nondopaminergic drugs like Mirtazipine, an antidepressant, Clonazepam for REM sleep disorder, botulinum toxin injections for drooling and dysphagia. The speech disturbances can be improved with cholinesterase inhibitors like rivastigmine, memantide and galantamine. Surgical advancements have been made for treating Parkinson’s disease which includes thalamotomy, pallidotomy and thalamic stimulation (Ahlskog2009; Jankovic & Aguilar 2008). “Clinical features and diagnosis” by J Jankovic gives an assessment of clinical features of Parkinson’s disease and the diagnostic criteria that is applied to detect the degree and severity of Parkinson’s disease. The major features of Parkinson disease are rest tremors, bradykinesia, rigidity and postural abnormalities. Other motor abnormalities are also faced by patients that include dysarthria, dysphagia, drooling, ocular abnormalities and respiratory dysfunctions. Non-motor features are also an important part of the clinical presentation and patients suffer from depression, dementia, and obsessive compulsive disorders and sleep disorder. Since, no laboratory or clinical test has yet been designed to test Parkinson’s disease; the clinical features are used for making a correct diagnosis. Previously Lewy bodies were used to confirm PD after death, however now the motor and non-motor symptoms along with responses to different doses of levodopa are used as a base for clinical diagnosis. It is important to discuss here the different types of Parkinsonian disorders which include idiopathic Parkinsonism, secondary type, heredodegenerative Parkinsonism and multiple system degeneration, where other systems are also involved in the neurodegenerative process. Apart from clinical diagnosis, MRI and CT scan of the brain can be done to assess the dopaminergic neuron loss (Jankovic 2007). In the other research paper, “Current approaches to the treatment of Parkinson’s disease” by Joseph Jankovic and L Giselle Aguilar, a detailed discussion about the recent medical and surgical treatment therapies have been published. Levodopa has been proven to give very fruitful results in reducing the symptoms of bradykinesia. However, dyskinesia associated with levodopa and the wearing off effect of this drug are some prominent adverse effects of this drug. If given in conjunction with Carbidopa it gives improved affects. Other important drugs are dopamine agonists and COMT inhibitors which are preferred due to their lesser complications and better results. Non-dopaminergic drugs can also be used to improve the non-motor symptoms like depression, obsessive-compulsive disorder, dysphagia and dysarthria. Keeping in view the action of glutamate in PD, anti-glutamatergic drugs have also been recommended because of their least neurotoxic affects. A future treatment strategy involving the use of neurotrophic drugs for PD appears as an effective treatment and would give beneficial results. Surgical interventions have also been made but they are not as established as the medical treatments (Jankovic & Aguilar 2008). The etiology of Parkinson’s disease has been discussed in “Converging Environmental and Genetic Pathways in Pathogenesis of Parkinson’s disease” by Burbulla and Kruger. The initial theory of development of Parkinson disease only from environmental causes or as a sporadic cause was changed after a group of genes was discovered causing both familial and sporadic cases of Parkinson’s disease. The group of genes causing autosomal dominant Parkinson’s disease includes the LRRK2, Parkin gene and SNCA gene. The consequent affects are on the protein aggregation and the degradation pathways of the proteins resulting into an abnormal protein accumulation with passage of time. Autosomal recessive genes causing mitochondrial gene aggregation or abnormalities are caused by Parkin gene, DJ-1 gene and PINK1 gene which affects the protein aggregation in the affected part of the brain. The environmental factors are also valuable in causing Parkinson’s disease. These cause inhibition of mitochondrial complex 1 or abnormal misfolding of proteins (Burbulla & Kruger 2011). Parkinson’s disease is a progressive disorder which has a late clinical onset. The recent evidences have proven its origin from not only environmental toxins but also from genetic causes. Some major genes have been established which lead to protein aggregation and mitochondrial dysfunction which include LRRK2, Parkin gene and SNCA gene. These are considered responsible for the familial cases while different types of mutations can also result in sporadic emergence of Parkinson’s disease. The role of environmental risk factors can also not be neglected and more researches are made in the involvement of caffeine consumption and its link to Parkinson’s disease. The most specific symptoms of Parkinson patients include slowness in movements which cause hindrance in daily activities, rest tremors along with postural tremors and rigidity. Other motor symptoms are also manifested by majority of the patients and are a result of neuronal abnormalities in respiration, swallowing, speech and neuropsychiatric disturbances. Mortality from Parkinson disease can be due to trauma caused by postural deformities or the non-motor consequences of Parkinson disease. Levodopa and dopamine agonists are recommended as the most potent drugs for Parkinson’s disease because of their effective outcomes. Many different drugs are also available which have a diverse mechanism of action; but all only help in reducing the symptoms, not curing the degradation of dopaminergic neurons in the substantia nigra. It is important to mention that a thorough examination and assessment of symptoms and signs of patent is necessary before stating any therapy to achieve the maximum amount of therapeutic benefits. Annotated Bibliography Ahlskog, J. E. (2009). Parkinson's disease treatment guide for physicians. Oxford: Oxford University Press. The author has written about the background and pathogenesis of the disease briefly in the start of his book. Later he has discussed the different strategies required to slow down and treat Parkinson symptoms. He has also put forward the different drugs, their mechanisms, pharmacodynamics and complications. Burbulla, L. F., & Kruger, R. (July 15, 2011). Converging environmental and genetic pathways in the pathogenesis of Parkinson's disease. Journal of the Neurological Sciences, 306, 1-8. The author discusses the relation between the genetic and environmental factors and the pathogenesis of Parkinson’s disease. They have also put forward the different genes that have been discovered and there affects on the morphology and pathological manifestations. Researches in environmental factors and their role in Parkinson’s disease development have been also put forward by the author. Goetz. C. ( 2011). The History of Parkinson’s disease: Early Clinical Descriptions and Neurological Therapies. Cold Spring Harbor Perspectives in Medicine. Retrieved from http://perspectivesinmedicine.org/content/1/1/a008862.full The author is associated with Department of Neurological Sciences and Department of Pharmacology, Rush University Medical Center, Chicago and has given a very detailed discussion of the historical development of the Parkinson’s disease. He has written about both clinical and treatment progression of the disease. Jankovic, J. (2007). Parkinson's disease: clinical features and diagnosis. Journal of Neurology, Neurosurgery and Psychiatry, 79, 4, 368-376. The author is a Professor in Department of Neurology at Parkinson’s disease Center and Movement Disorders Clinic, Texas. He has independently researched about the cardinal clinical features of the Parkinson’s disease and how the other associated symptoms can be used as a basis for diagnosing Parkinson’s disease at a clinical level. Jankovic, J., & Aguilar, L. G. (2008). Current approaches to the treatment of Parkinson's disease.Neuropsychiatric Disease and Treatment, 4, 4, 743-757. The author writes about the recent treatment therapies applicable for Parkinson’s disease. The medical as well as the surgical methods have been discussed. Some future treatments have also been mentioned which are being considered for the treatment of this disease. Read More