Parkinson's Disease

Parkinson’s disease (PD) is the second most common neurodegenerative brain disorder affecting about 1% of individuals over the age of sixty and causing a dramatic decrease in life expectancy1. PD is pathologically marked by the loss of dopamine producing neurons in the substantia nigra, a region in the midbrain. This disease is classically categorized as a movement disorder since affected individuals normally exhibit postural instability, tremor at rest, and akinesia. Currently, medication such as levodopa and dopamine agonists are use to manage motor related symptoms at early stages, though these treatments become ineffective as the disease progresses. A rapidly aging demographic along with progress in the fields of genetics, molecular biology and neuroimaging has spurred a number of developments in PD research. The cause of PD is currently unknown. There are a number of genetic and environmental risk factors associated with the disease though the majority of cases remain idiopathic in nature2. Due to its unknown etiology, focus has been on developing procedures for early detection and characterizing neural changes that may lead to more effective treatments. Specific focus will be given to the genetic etiology of PD, potential causes at the protein level marked by α-synuclein pathologies, non-motor symptoms, differential brain activation associated with the disease, early detection techniques, and effective treatments such as deep brain stimulation.

1. De Lau LML, Breteler MMB. Epidemiology of Parkinson disease. Lancet Neurology (2006) 5: 525-535.
2. Crosiers D, Theuns J, Cras P, Van Broeckhoven C. Parkinson disease: Insights in clinical, genetic and pathological features of monogenic disease subtypes. Journal of Chemical Neuroanatomy (2011) 42: 131-141

Deep-Brain-Stimulation (DBS) Treatment for Parkinson's Disease

main article: Deep-Brain-Stimulation (DBS) Treatment for Parkinson's Disease
author: Joseph Blommesteyn

Treating PD with DBS
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Standard equipment used for DBS.

Parkinson's disease (PD) is a neurodegenerative disease that currently has no known cure. The treatment for PD aims to reduce the severity of the motor symptoms, and generally involves a multi-faceted approach to improve the quality of life for patients in both social and medical aspects as PD is chronic and debilitating.
The first steps in treating PD involve a pharmacologic intervention that often relies on a mix of drugs to alleviate the motor deficits. These drugs act on the dopaminergic system of neurons, and are usually dopamine precursors, dopamine agonists or MAO-B inhibitors[1]. Levodopa is a dopamine precursor that is widely used because of its effectiveness, but prolonged usage leads to reduced effectiveness and the emergence of dyskinesia. When the patient begins to exhibit the Levodopa side-effects, surgical techniques are often relied on to relieve the motor symptoms from both PD and the drug treatment[2].
Surgically implanting electrodes for deep-brain stimulation (DBS) relieves almost all parkinsonian symptoms for PD patients who can no longer handle their medication, and is preferred over ablative procedures [2].

1. The National Collaborating Centre for Chronic Conditions, ed. (2006)."Symptomatic pharmacological therapy in Parkinson’s disease". Parkinson's Disease. London: Royal College of Physicians. pp. 59–100.
2. Yianni, J. and Aziz, T. (2003) Surgical treatment of Parkinson’s Disease. ACNR 2, 21-22.

Differential Activation of Brain Areas in Parkinson's Disease

main article: Differential Activation of Brain Areas in Parkinson's Disease
author: Herman Tang

Complexity in Brain Activation
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If understanding how brain works was analogous to building a puzzle,
we'd only be starting to gather the pieces

Parkinson's Disease is a multisystem neurodegenerative disorder that presents with a diverse set of symptoms ranging from tremor and bradykinesia to cognitive impairment, hallucinations , sleep disorders and dementia . It is the second most prevalent neurodegenerative disease behind Alzheimer's and is becoming more important as the population ages.[1]

Recent studies have made use of various forms of imaging such as functional magnetic resonance imaging[2], transcranial sonography[3], diffusion tensor imaging[4], and single-photon emission computed tomography[5] to evaluate the integrity and activity of brain networks and regions. In addition to shedding light on the pathologies underlying symptomatic manifestations of the disease, both functional and structural imaging could be used as potential tools for diagnosis in a clinical setting.

1. Yarnall, A., Archibald, N., Burn, D. 2012. Parkinson’s disease. Medicine 40(10):529-535.
2. Muller, J., L., Deuticke, C., Putzhammer, A., Roder, C., Hajak, G., Winkler, J. 2003. Schizophrenia and Parkinson's disease lead to equal motor-related changes in cortical and subcortical brain activation: An fMRI fingertapping study. Psychiatry and Clinical Neurosciences. 57:562-568.
3. Berg, D. 2006. In vivo detection of iron and neuromelanin by transcranial sonography - a new approach for early detection of substantia nigra damage, Journal of Neural Transmission. 113:775-780.
4. Zhan, W., Kang, G., A., Glass, G., A., Zhang, Y., Shirley, C., Millin, R., Possin, K., L., Nezamzadeh, M., Weiner, M., W., Marks, W., J., Schuff, N. 2011. Regional Alterations of Brain Microstructure in Parkinson's Disease Using Diffusion Tensor Imaging. Movement Disorders. 27(1): 90-97
5. Ekman, U., Eriksson, J., Forsgren, L., Mo, S., J., Riklund, K., Nyberg, L. 2012. Functional brain activity and presynaptic dopamine uptake in patients with Parkinson's disease and mild cognitive impairment: a cross-sectional study. The Lancet Neurology. 11:679-687.

Genetic Etiology of Parkinson's Disease

main article: Genetic Etiology of Parkinson's Disease
author: alinag

PD Phenotypes associated with specific mutations
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Flowchart for familial parkinsonism phenotypes. Adapted from Crosiers et al. (2011).

Parkinson’s disease (PD) is the second most common neurodegenerative brain disorder affecting about 1% of individuals over the age of sixty and causing a dramatic decrease in life expectancy [1]. It is classically categorized as a movement disorder since affected individuals normally exhibit postural instability, tremor at rest, and akinesia. These symptoms are generally attributed to the loss of dopamine producing neurons in the substantia nigra, a region in the midbrain. Despite developments in symptom management, the cause of PD is not currently known. Research is currently directed towards finding the genetic etiology of PD in hopes of establishing its molecular pathology, implementing procedures for early detection and developing more effective treatments. Classic linkage studies and positional cloning strategies have led to the discovery of multiple genes that cause monogenetic autosomal-dominant or autosomal-recessive forms of PD. These genetic analyses have also yielded rare genetic variants and environmental risk factors for PD. However, these known Mendelian forms of PD and other identified risk factors only explain 20-30% of cases in the general population. The advent of new genetic techniques such as genome wide association studies and whole genome sequencing promises to uncover many common and rare genetic variants that may cause or predispose one to PD[2].

1. De Lau LML et al. Epidemiology of Parkinson disease. Lancet Neurology (2006) 5: 525-535.
2. Gasser T et al. . Milestones in PD Genetics. Movement Disorders (2011) 28 (6): 1042-1048.

Non-Motor Parkinsons Symptoms

main article: Non-Motor Parkinsons Symptoms
author: Igbinosa Uwadiae

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Image Source

Parkinson’s disease was believed to be a, motor debilitating disease mainly dealing with loss of dopaminergic neurons in the substantial Nigra[1]. However recent developments have shown that Parkinson’s disease seems to have an effect on other regions of the brain, associated with non-motor control[1]. These symptoms can often times precede the onset of motor related symptoms by up to 10 years[2]. Characteristic pre-motor symptoms include: Sleep Disorder based symptoms, Autonomous Dysfunction symptoms and Neuropsychological symptoms[3]. These symptoms can also occur in comorbid manner, to the extent that the establishment of one symptom leads to the occurrence of another symptom, this is particularly implicit in both sleeping disorders and neuropsychological disorders[3]. Current studies have shown that both sleep disorder and autonomous dysfunction may play an integral role as neurological markers for the potential development of Parkinson’s disease.  This, researchers believe could be vital in the development and implementation of psychoactive drug or Deep-Brain Stimulation treatments to target the disease in its earliest state[4].A definite hypothesis on the causes of these symptoms is still unknown; however multiple studies have depicted the notion of dopamine deficiency in different regions of the brain as the inherent cause of these non-motor symptoms[4].

1. Weerkamp, N, Nihjof, A., & Tissingh, J. (2012). Non Motor Symptoms of Parkinson ’s disease. Atrium Medisch Centrum Parkstad, (2012) 1:156-158.
2. Videnovic, A, & Golombek, D Circadian and sleep disorders in Parkinson's disease. Experimental Nuerology.(2012).
3. Bernal-Pacheco O, Limotai N, Go C, Fernandez H. Nonmotor Manifestations in Parkinson Disease. Wolters Kluwer.(2012) 1:1-16.
4. Sharabi Y, Goldstein D,Barbara K, Olandi B, Saleem A, Pacak K, Eisenhofer G.Cardiac sympathetic denervation preceding motor signs in Parkinson disease. Clevland Clinic Journal Of Medicine.(2007)17:118-121

α-Synucleinopathy in Parkinson's Disease

main article: α-Synucleinopathy in Parkinson's Disease
author: Hyun Kim Kim

What is a Parkinson's disease?
Overview of what a Parkinson's disease is. This introductory video provides basic
understanding of pathophysiology of PD that will aid in understanding role of α-Syn.

Virtually all sporadic and familial forms of Parkinson’s disease (PD) are associated with two major disease processes: selective loss of midbrain dopamine (DA) neurons in substantia nigra pars compacta (SNpC), and accumulations of intraneuronal inclusions known as Lewy bodies (LB)[1]. While the relationship between these two conditions were largely unexplored in the past, recent researche point to a strong causal relationship. More specifically, scientists believe that α-synucleins (α-Syn), a protein of primary component in LB, may be the cause of PD. Normally α-Syn function to maintain proper synaptic processes; however, certain changes in its structure initiates a cascade of pathological events commonly referred to as α-synucleinopathy. Converging lines of evidence suggest loss of DA neurons in SNpC of PD patients are the result of the α-synucleinopathy[2]. As such, it is hoped that future insights into α-Syn and their mechanism of pathology will help shed new light in developing effective therapies for PD of which we know little.

1. J. Burre, M. Sharma, T. Tsetsenis, V. Buchman, M.R. Etherton, T.c. Sudhof. α-Synuclein promotes SNARE-complex assembly in vivo and in vitro. Science (2010) 329:1663-1667
2. K.C. Luk, V. Kehm, J. Carroll, B. Zhang, P. O'Brien, J.Q. Trojanowski, V.M.Y. Lee. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science (2012) 338:949-953.

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