Journal of Parkinson's Disease - Volume 2, issue 4

Authors: Kanaan, Nicholas M. | Manfredsson, Fredric P.

Article Type: Review Article

Abstract: The discovery that alpha-synuclein (α-syn) is the primary component of the neuropathological hallmarks of Parkinson's disease (PD) and the identification of α-syn mutations in numerous inherited forms of PD has positioned α-syn at the top of the list of important factors in the pathogenesis of PD. Based on the pathological accumulation of α-syn in the brains of patients, the field is currently focused on therapeutic strategies that aim to reduce or eliminate α-syn. However, recent evidence suggests α-syn is a critical protein in neuron (i.e. dopamine neurons) survival and that maintaining a certain level of biologically functional α-syn is an …important consideration in targeting α-syn for therapies. Despite the widespread interest in α-syn, the normal biological functions remain elusive, but a large body of work is focused on addressing this issue. In this review, we will discuss the current evidence related to α-syn function, α-syn folding and aggregation, and α-syn's role in disease. Finally, we will propose a relatively novel hypothesis on the pathogenesis of PD that hinges upon the premises that functional α-syn is critical to cell survival and that a reduction in biologically functional α-syn, whether through aggregation or reduced expression, may lead to the neurodegeneration in PD. Show more

Keywords: Parkinson's disease, alpha-synuclein, neurodegenerative disease, dopamine, lewy body

DOI: 10.3233/JPD-012138

Citation: Journal of Parkinson's Disease, vol. 2, no. 4, pp. 249-267, 2012

Authors: Perju-Dumbrava, L.D. | McDonald, M. | Kneebone, A.C. | Long, R. | Thyagarajan, D.

Article Type: Short Communication

Abstract: Although effective deep brain stimulation of the subthalamic nucleus (STN-DBS) is reported in G2019S leucine-rich repeat kinase 2 (LRRK2) parkinsonism, response to surgery in other LRRK2 mutations has not been previously reported. We present an affected individual from the Lincolnshire pedigree (Y1699C), on whom bilateral STN-DBS was performed to control severe motor fluctuations and dyskinesias. He showed a marked improvement in Unified Parkinson's Disease Rating Scale (UPDRS) Part III scores in the “on” and “off” states, sustained for more than three years. Bilateral STN-DBS in LRRK2-parkinsonism with the Y1699C mutation can be as effective as in sporadic PD.

Keywords: Parkinson's disease, PARK8, leucine-rich repeat kinase 2, deep brain stimulation, subthalamic nucleus

DOI: 10.3233/JPD-012121

Citation: Journal of Parkinson's Disease, vol. 2, no. 4, pp. 269-271, 2012

Authors: Rana, Abdul Qayyum | Khan, Adeel | Uppal, Russell | Galange, Patrick | Yosuf, Muhammad Saad | Siddiqui, Ishraq | Jesudasan, Ajantha | Rana, Afshan Nazli | Abounaja, Mohammad | Hafez, Kevin | Rana, Mohammed Abdullah

Article Type: Research Article

Abstract: Background: Despite being an important non-motor symptom of PD, pain remains largely understudied in PD patients. Experiencing symptoms of pain is highly disruptive of general functioning, as it may hinder both physical prowess and psychological well-being. Although pain is prevalent in the otherwise healthy geriatric population, its increased presence in PD, and the difficulty it poses when combined with other hallmark motor symptoms necessitates further investigation. An improved understanding of factors that aggravate pain, and methods that alleviate discomfort may provide significant insight on the basis of pain in PD. Such information may ultimately allow healthcare professionals to achieve the …goal of improved PD patient management. Objective: To study the associations between various factors and pain in a Parkinson's disease (PD) patient population. Methods: This study investigated 121 PD patients, of which 80 reported to have pain in at least one area of the body. Exclusion criteria included patients suffering from external causes of pain, such as trauma and patients with cognitive impairment whose accounts may not have been reliable. Further inquiry determined the etiology of pain, as well as aggravating and alleviating factors. The efficacies of pharmacological or non-pharmacological therapies were assessed through additional questioning. Individuals were also asked whether their pain was unintentionally affected by other measures, such as prescribed PD medications. Results: Multiple linear regression analysis with a Wald test value of 4.070 (p = 0.044) demonstrated a statistically significant relationship between the administration of analgesics in patients with high reported pain and their pain relief. However, patients who experienced moderate pain did not exhibit any statistically significant levels of pain relief with the use of analgesics (Wald = 2.097, p = 0.148). Similarly, non-pharmacological therapies, PD medicine, and comorbidities showed no statistically significant correlations with pain relief. Conclusions: Physicians should be aware of the physiological and psychological factors that form major components of pain relief, and that patient education and support are critical to successful treatment programs. Show more

Keywords: Parkinson's disease, pain, health policy and practice, medicine, movement disorders

DOI: 10.3233/JPD-2012-012125

Citation: Journal of Parkinson's Disease, vol. 2, no. 4, pp. 273-279, 2012

Authors: Rana, Abdul Qayyum | Athar, Aysha | Owlia, Aida | Siddiqui, Ishraq | Awan, Naeem | Fattah, Abdul | Rana, Mohammed A.

Article Type: Research Article

Abstract: Parkinson's disease (PD) is a neurodegenerative illness characterized by various non-motor symptoms that may contribute to disability, impaired quality of life and shortened life expectancy. The aim of present study was to determine the relative prevalence of common non-motor symptoms in various ethnic groups. A retrospective chart analysis was performed on Parkinson's disease patients where a total of 314 PD patients from six ethnic categories were examined for the occurrence of anxiety, visual hallucinations, nocturia, drooling and dementia. Our results show that anxiety in PD patients was correlated with their ethnicity classification. Interesting trends were observed with respect to nocturia …and dementia symptoms and no significant differences were found between ethnic groups for visual hallucinations and drooling. Our study shows that non-motor symptoms of Parkinson's disease are prevalent across all ethnic groups, and except anxiety there may not be any impact of ethnicity on dementia, nocturia, drooling, and visual hallucinations. Show more

Keywords: Ethnology, anxiety, visual hallucinations, nocturia, drooling, dementia, Parkinson's disease

DOI: 10.3233/JPD-129002

Citation: Journal of Parkinson's Disease, vol. 2, no. 4, pp. 281-285, 2012

Authors: Patel, Mital Y. | Panchal, Hirenkumar V. | Ghribi, Othman | Benzeroual, Kenza E.

Article Type: Research Article

Abstract: Background: Parkinson's disease (PD) is characterized by excessive deposition of neuritic plaques known as Lewy bodies of which α-synuclein is the major contributor to neuronal death. Both oxidative stress and cytokines signaling have been proposed to play an important role in α-synuclein-induced neuronal death in MPTP and PD-related neuronal cell death. Fisetin, a natural polyphenol, possesses antioxidant, anti-inflammatory, and anti-apoptotic properties. However, the molecular neuroprotective mechanisms of fisetin against MPTP-induced cytotoxicity are still unknown. Objective: The present study investigated the inhibitory effect of fisetin on MPTP/MPP+-induced neurotoxicity in PC12 cells. Methods: Cells were pretreated with varying concentrations of fisetin prior …exposure to MPTP/MPP+. Cell viability and apoptosis were investigated using MTT assay and DNA fragmentation. The expression and release of transcription factor, pro-inflammatory cytokines, and apoptotic mediators were assessed using western blot analysis and ELISA. Results: Results showed that a pre-treatment with fisetin before exposure to MPTP/MPP+ significantly decreased MPTP/MPP+-induced cytotoxicity and cell death probably by decreasing α-synuclein expression. Mechanisms study showed that fisetin has the potential to inhibit several apoptotic and inflammatory pathways, which play important roles in the initiation and progression of PD. Conclusions: Altogether, these observations indicate that fisetin is capable of attenuating α-synuclein levels and promoting neuroprotective effects, meanwhile also present some insights into the potential signaling pathways that are involved. Thus, these findings support the role of natural polyphenols in preventive and/or complementary therapies for neurodegenerative diseases. Show more

Keywords: Fisetin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), MPP+, PC12 cells, Apoptosis, pro-inflammatory cytokines, NF-κB inhibitor, neurodegeneration, Parkinson's disease

DOI: 10.3233/JPD-012110

Citation: Journal of Parkinson's Disease, vol. 2, no. 4, pp. 287-302, 2012

Authors: Nielsen, Susan Searles | Checkoway, Harvey | Butler, Rondi A. | Nelson, Heather H. | Farin, Federico M. | Longstreth Jr., W.T. | Franklin, Gary M. | Swanson, Phillip D. | Kelsey, Karl T.

Article Type: Research Article

Abstract: Background: Long interspersed nucleotide element-1 (LINE-1) retrotransposons are located throughout the human genome. Those retaining an intact 5′ promoter can copy and insert themselves into the DNA of neural progenitor cells that express tyrosine hydroxylase, which may influence differentiation and survival of these cells. LINE-1 promoter methylation is associated with decreased LINE-1 propagation. Objective: To investigate whether LINE-1 promoter methylation is associated with Parkinson's disease (PD). Methods: We compared LINE-1 methylation profiles in blood mononuclear cells between 292 newly diagnosed PD cases and 401 unrelated, neurologically normal controls, all non-Hispanic Caucasians in western Washington state. Results: Overall, PD was not …associated with percent methylation of the LINE-1 promoter. However, the predictable inverse association between PD and ever smoking tobacco was strongest for men and women with the lowest LINE-1 promoter methylation, and less apparent as LINE-1 methylation increased. Underlying this possible interaction, ever regularly smoking tobacco was associated with decreased LINE-1 methylation in controls (age- and sex-adjusted linear regression β = −0.24, 95% confidence interval [CI] −0.43, −0.04), but not in cases (β = 0.06, 95% CI −0.17, 0.28, interaction p = 0.06). Conclusion: PD cases may have innate differences in their ability to respond to tobacco smoke. Show more

Keywords: DNA methylation, idiopathic Parkinson's disease, long interspersed nucleotide elements, smoking

DOI: 10.3233/JPD-012129

Citation: Journal of Parkinson's Disease, vol. 2, no. 4, pp. 303-308, 2012

Authors: Heuer, Andreas | Dunnett, Stephen B.

Article Type: Research Article

Abstract: Background: Parkinson's disease (PD) is most commonly modelled in rats via injection of the neurotoxin 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Assessment of lateralised choice reaction time is usually conducted in the 9 hole box, a highly specialized apparatus that is not widely available in many behavioural laboratories. The retractable lever Skinner box on the other hand is more readily available and may have the additional advantage of faster training of animals. Objective: The present study assesses the performance of lesioned rats on a lateralised choice reaction time task that allows for quantitative assessment of the behavioural profile of …models of neurodegenerative diseases in the retractable lever Skinner box. Methods: Here we compared the post lesion performance of pretrained female Lister hooded rats that received unilateral 6-OHDA lesions to the medial forebrain bundle and untreated controls on the choice reaction time task conducted in the Skinner box. Results: Lesioned animals displayed impairments in contralateral accuracy, a reduced number of usable trials, as well as a slowing down of contralateral reaction and bilateral movement time latencies. Conclusions: The findings presented allow greater comparison between laboratories, and may be useful for the investigation of treatment strategies and remedies on this model of PD. Show more

Keywords: Parkinson's disease, 6-OHDA, operant behaviour, Skinner box, choice reaction time, dopamine, rat

DOI: 10.3233/JPD-2012-012133

Citation: Journal of Parkinson's Disease, vol. 2, no. 4, pp. 309-320, 2012

Authors: Khoo, Sok Kean | Petillo, David | Kang, Un Jung | Resau, James H. | Berryhill, Brian | Linder, Jan | Forsgren, Lars | Neuman, Leslie A. | Tan, Aik Choon

Article Type: Research Article

Abstract: Background: The current “gold-standard” for Parkinson's disease (PD) diagnosis is based primarily on subjective clinical rating scales related with motor features. Molecular biomarkers that are objective and quantifiable remain attractive as clinical tools to detect PD prior to its motor onsets. Objective: Here, we aimed to identify, develop, and validate plasma-based circulating microRNA (miRNAs) as biomarkers for PD. Methods: Global miRNA expressions were acquired from a discovery set of 32 PD/32 controls using microarrays. k-Top Scoring Pairs (k-TSP) algorithm and significance analysis of microarrays (SAM) were applied to obtain comprehensive panels of PD-predictive biomarkers. TaqMan miRNA-specific real-time PCR assays were …performed to validate the microarray data and to evaluate the biomarker performance using a new replication set of 42 PD/30 controls. Data was analyzed in a paired PD-control fashion. The validation set was composed of 30 PD, 5 progressive supranuclear palsy, and 4 multiple system atrophy samples from a new clinical site. Results: We identified 9 pairs of PD-predictive classifiers using k-TSP analysis and 13 most differentially-expressed miRNAs by SAM. A combination of both data sets produced a panel of PD-predictive biomarkers: k-TSP1 (miR-1826/miR-450b-3p), miR-626, and miR-505, and achieved the highest predictive power of 91% sensitivity, 100% specificity, 100% positive predicted value, and 88% negative predicted value in the replication set. However, low predictive values were shown in the validation set. Conclusions: This proof-of-concept study demonstrates the feasibility of using plasma-based circulating miRNAs as biomarkers for neurodegenerative disorders such as PD and shows the challenges of molecular biomarker research using samples from multiple clinical sites. Show more

Keywords: Circulating microRNAs, plasma, biomarkers, Parkinson's disease

DOI: 10.3233/JPD-012144

Citation: Journal of Parkinson's Disease, vol. 2, no. 4, pp. 321-331, 2012

Authors: Lindgren, Niklas | Francardo, Veronica | Quintino, Luis | Lundberg, Cecilia | Cenci, M. Angela

Article Type: Research Article

Abstract: Background: Glial cell line-derived neurotrophic factor (GDNF) is the most promising neurotrophin for restorative treatments in Parkinson's disease, but its biological effects are not completely understood. Objective: To define a model of GDNF gene therapy in the mouse, we studied the long-term effects of lentiviral GDNF delivery in mice with striatal 6-hydroxydopamine (6-OHDA) lesions. Methods: Lentiviral vectors coding for GDNF or green fluorescent protein (GFP) were injected unilaterally in the striatum two weeks prior to the 6-OHDA lesion. Mice were monitored on tests of spontaneous activity and amphetamine-induced rotation at 1, 4, 10 and 35 weeks post-lesion. Brains were processed …immunohistochemically for tyrosine hydroxylase (TH) and markers of extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation at the same time points. Results: Lentiviral GDNF significantly inhibited both spontaneous and amphetamine-induced rotation. Compared to the control vector, lentiviral GDNF resulted in a partial protection of TH-positive cells in the substantia nigra, and in a nearly total restoration of striatal TH immunostaining by 35 weeks. A progressive sprouting of TH-positive neurites occurred in both the globus pallidus and the substantia nigra, reaching a 4-5 fold increase above controls by 35 weeks. This effect was paralleled by a long-term supranormal activation of ERK1/2 and its downstream target, phospho-Ser31 TH. Conclusions: Lentiviral GDNF delivery produced robust long-term signaling responses and neurorestoration. This experimental model of GDNF gene therapy will be particularly suitable to study the molecular mechanisms of dopaminergic fiber sprouting, a long-term response to GDNF delivery that also occurs in Parkinson's disease patients. Show more

Keywords: Neurotoxin, neuroprotection, rodent, mitogen-activated protein kinases, MAPK, trophic factor, GDNF

DOI: 10.3233/JPD-012146

Citation: Journal of Parkinson's Disease, vol. 2, no. 4, pp. 333-348, 2012

Authors: Modak, Anil | Durso, Raymon | Josephs, Ephraim | Rosen, David

Article Type: Research Article

Abstract: Background: Peripheral carbidopa (CD) levels directly impact on central dopamine (DA) production in Parkinson disease (PD) through extracerebral inhibition of dopa decarboxylase (AADC) resulting in an increase in levodopa (LD) bioavailability. Objective: Recent data suggests that higher CD doses than those presently used in PD treatment may result in improved clinical response. Optimizing CD doses in individual patients may, therefore, result in ideal individualized treatment. Methods: A single center, randomized, double-blind study was carried out recruiting 5 Parkinson's disease (PD) patients already on LD/CD and 1 treatment naïve PD patient using stable isotope labeled LD-1-13 C as a substrate for …a noninvasive breath test to evaluate individual AADC enzyme activity. Each patient was studied five times, receiving 200 mg LD-13 C at each visit along with one of five randomized CD doses (0, 25, 50, 100 and 200 mg). The metabolite 13 CO2 in breath was measured for evaluating AADC enzyme activity and plasma metabolite levels for LD-13 C and homovanillic acid (HVA) were measured for 4 hours. Results: HVA in plasma and 13 CO2 in breath are metabolic products of LD. We found a significant positive correlation of 13 CO2 DOB AUC0-240 with serum HVA AUC0-240 following the oral dose of LD-1-13 C for all 5 doses of CD (r2 = 0.9378). With increasing inhibition of AADC enzyme activity with CD, we observed an increase in the plasma concentration of LD. We found an inverse correlation of the 13 CO2 DOB AUC with serum LD-13 C AUC. Our studies indicate the optimal dose of CD for maximal suppression of AADC enzyme activity can be determined for each individual from 13 CO2 generation in breath. Conclusions: The LD-breath test can be a useful noninvasive diagnostic tool for evaluation of AADC enzyme activity using the biomarker 13 CO2 in breath, a first step in personalizing CD doses for PD patients. Show more

Keywords: Parkinson's disease, personalized therapy, dopa decarboxylase, L-DOPA-$^{13}$C breath test

DOI: 10.3233/JPD-012132

Citation: Journal of Parkinson's Disease, vol. 2, no. 4, pp. 349-356, 2012