Journal of Parkinson's Disease - Volume 3, issue 2

Authors: Paisán-Ruiz, Coro | Lewis, Patrick A. | Singleton, Andrew B.

Article Type: Review Article

Abstract: In 2004 it was first shown that mutations in LRRK2 can cause Parkinson's disease. This initial discovery was quickly followed by the observation that a single particular mutation is a relatively common cause of Parkinson's disease across varied populations. Further genetic investigation has revealed a variety of genetic ties to Parkinson's disease across this gene. These include common alleles with quite broad effects on risk, likely through both alterations at the protein sequence level, and in the context of expression. A great deal of functional characterization of LRRK2 and disease-causing mutations in this protein has occurred over the last 9 …years, and considerable progress has been made. Particular attention has been paid to the kinase activity of LRRK2 as a therapeutic target, and while it is no means certain that this is viable target it is likely that this hypothesis will be tested in clinical trials sooner rather than later. We believe that the future goals for LRRK2 research are, while challenging, relatively clear and that the next 10 years of research promises to be perhaps more exciting than the last. Show more

Keywords: LRRK2, associated phenotype, disease risk, biology, future challenges, Parkinson's disease, parkinsonism, genetics

DOI: 10.3233/JPD-130192

Citation: Journal of Parkinson's Disease, vol. 3, no. 2, pp. 85-103, 2013

Authors: Callesen, Mette Buhl | Scheel-Krüger, Jørgen | Kringelbach, Morten L. | Møller, Arne

Article Type: Review Article

Abstract: Throughout the past decade it has been recognized that dopaminergic medication administered to remedy motor symptoms in Parkinson's disease is associated with an enhanced risk for impulse control disorders and related compulsive behaviors such as hobbyism, punding, and the dopamine dysregulation syndrome. These complications are relatively frequent, affecting 6–15.5% of patients, and they most often appear, or worsen, after initiation of dopaminergic therapy or dosage increase. Recently, impulse control disorders have also been associated with subthalamic nucleus deep brain stimulation. Here we present a systematic overview of literature published between 2000 and January 2013 reporting impulse control disorders in Parkinson's …disease. We consider prevalence rates and discuss the functional neuroanatomy, the impact of dopamine-serotonin interactions, and the cognitive symptomatology associated with impulse control disorders in Parkinson's disease. Finally, perspectives for future research and management of impulse control disorders in Parkinson's disease are discussed. Show more

Keywords: Impulse control disorders, Parkinson disease, dopamine, serotonin, neuroanatomy, decision making

DOI: 10.3233/JPD-120165

Citation: Journal of Parkinson's Disease, vol. 3, no. 2, pp. 105-138, 2013

Authors: Djamshidian, Atbin | O'Sullivan, Sean S. | Foltynie, Thomas | Aviles-Olmos, Iciar | Limousin, Patricia | Noyce, Alastair | Zrinzo, Ludvic | Lees, Andrew J. | Averbeck, Bruno B.

Article Type: Research Article

Abstract: Background: Dopamine agonist therapy is the main risk factor for impulse control disorders in Parkinson's disease (PD). However, it is unclear whether bilateral deep brain stimulation of the subthalamic nucleus also causes impairment in decision making. Objectives: To assess the role of dopamine agonist therapy and deep brain stimulation on reflection impulsivity in non-demented patients with PD. Methods: We recruited 61 PD patients, 20 treated with L-dopa in combination with a dopamine agonist, 14 taking L-dopa monotherapy, a further 16 PD patients with bilateral subthalamic nucleus deep brain stimulation treated with L-dopa in combination with a dopamine agonist, and 11 …PD patients with bilateral subthalamic nucleus deep brain stimulation taking L-dopa but not a dopamine agonist. Results were compared with 18 healthy controls. Patients who had evidence of impulsive compulsive behaviour were excluded. Reflection impulsivity was assessed with the beads task, which is a validated information sampling task. Results: All patients treated with a dopamine agonist gathered significantly less information and made more irrational decisions than all other groups regardless of whether they had surgical treatment. Conclusions: Our results imply that dopamine agonist therapy but not deep brain stimulation leads to “reflection impulsivity” in PD. Show more

Keywords: Deep brain stimulation, neuropsychology, Parkinson's disease

DOI: 10.3233/JPD-130178

Citation: Journal of Parkinson's Disease, vol. 3, no. 2, pp. 139-144, 2013

Authors: Dzamko, Nicolas | Chua, Germaine | Ranola, Madelaine | Rowe, Dominic B. | Halliday, Glenda M.

Article Type: Research Article

Abstract: A significant number of autosomal dominantly inherited Parkinson's disease (PD) cases are due to mutations in the leucine-rich repeat kinase 2 (LRRK2) gene. In cells, these pathogenic mutations have a number of differing effects on LRRK2 enzymatic activity and protein stability. In particular, five of the six described pathogenic LRRK2 mutations ablate the constitutive phosphorylation of LRRK2 on Ser910 and Ser935, two residues required for binding of LRRK2 to 14-3-3 proteins. This suggests a potential pathogenic role for these residues. However, LRRK2 kinase inhibitors, which have shown early promise as neuroprotective agents, also ablate the phosphorylation of Ser910 and Ser935. …Additionally, LRRK2 is phosphorylated on Ser910 and Ser935 following activation of the inflammatory toll-like receptor pathway and inflammatory cytokines are often increased in PD patients. Whether LRRK2 protein or phosphorylation is altered in idiopathic PD is unknown. We therefore measured LRRK2 protein and its phosporylation in peripheral blood mononuclear cells (PBMCs) from 33 idiopathic Parkinson's disease patients and 27 age-matched controls. We found no significant difference in total LRRK2 protein levels in PBMCs from PD patients compared to controls. Furthermore, total LRRK2 protein expression was not effected by age, disease duration, disease severity or levodopa medication. The amount of phosphorylation on LRRK2 at both Ser910 and Ser935 correlated highly with total LRRK2 levels and was also unchanged in PD patients. Therefore, changes in LRRK2 Ser910/Ser935 phosphorylation in PBMCs are unlikely to contribute to idiopathic Parkinson's disease or be of utility as a disease biomarker. However, the invariance of Ser910 and Ser935 phosphorylation in PD PBMC's suggests that these residues could be used as pharmacodynamic biomarkers for the effectiveness of LRRK2 kinase inhibitors in patients. Show more

Keywords: Kinase, phosphorylation, monocyte, lymphocyte, inflammation, antibody. LRRK2, Parkinson's disease, neurodegeneration, immunity

DOI: 10.3233/JPD-130174

Citation: Journal of Parkinson's Disease, vol. 3, no. 2, pp. 145-152, 2013

Authors: Crizzle, Alexander M. | Classen, Sherrilene | Lanford, Desiree N. | Malaty, Irene A. | Okun, Michael S. | Wang, Yanning | Wagle Shukla, Aparna | Rodriguez, Ramon L. | McFarland, Nikolaus R.

Article Type: Research Article

Abstract: Background: The primary influence of motor symptoms on driving performance remains unclear due to the inconsistent use of various motor rating scales used in prior studies. Objective: This study aimed to determine which of three measures utilized in PD, the Unified Parkinson's Disease Rating Scale (UPDRS) motor section; the Modified Hoehn and Yahr; and the Rapid Paced Walk Test would best predict pass/fail outcomes on a road test in a sample of PD drivers. Methods: All participants (N = 55; 79% men) completed a road test. Receiver Operating Characteristics were then contrasted for all subjects based on assessments from all …three disease severity indices. MMSE scores were then modelled with significant disease severity measures (if any) to determine if the predictive accuracy could be improved. Results: The Rapid Paced Walk Test and the Modified Hoehn & Yahr both predicted pass/fail outcomes on the road test (Area under the curve of 0.73 and 0.82, respectively). UPDRS motor scores, however, did not predict safe driving. When optimal cut-off points on the Modified Hoehn & Yahr (≥2.5) and Rapid Paced Walk Test (>6.22 seconds) were modelled with MMSE scores indicative of mild cognitive impairment (<27), the model accurately classified 92% and 100% as failing the road test, respectively. Conclusion: Although the Rapid Paced Walk Test had a slight advantage in differentiating between pass/fail outcomes compared to the Modified Hoehn & Yahr, both tests alone cannot be used in isolation to predict driving safety. Predictive accuracy can be improved using both select cut-off points on the Modified Hoehn & Yahr and Rapid Paced Walk test with MMSE scores in PD drivers. Though these findings are useful, an on-road test is still the gold standard, and screening should always be followed by formal testing. Show more

Keywords: Automobile driving, Parkinson's disease, gait/postural balance, cognition

DOI: 10.3233/JPD-120152

Citation: Journal of Parkinson's Disease, vol. 3, no. 2, pp. 153-160, 2013

Authors: Stuckenholz, Vanessa | Bacher, Michael | Balzer-Geldsetzer, Monika | Alvarez-Fischer, Daniel | Oertel, Wolfgang H. | Dodel, Richard C. | Noelker, Carmen

Article Type: Research Article

Abstract: Background: Parkinson's disease (PD) is associated with neurodegeneration of dopaminergic neurons and an accompanying neuroinflammatory process in the substantia nigra (SN). The cholinergic anti-inflammatory signalling pathway allows the autonomic nervous system to modulate immunologic stimuli and inflammatory processes. A major component of this pathway is the α7 nicotinic acetylcholine receptor (α7 nACh receptor), which is expressed on immune cells such as microglia. Objective: To determine the role of this cholinergic anti-inflammatory signalling pathway, we investigated the effects of the selective α7 nACh agonist PNU-282987 and of the non-competitive nACh antagonist mecamylamine on microglia-induced neuroinflammation and toxin-induced degeneration of dopaminergic neurons …in a mouse model of PD. Methods: PNU-282987, mecamylamine or placebo administration was started one day before MPTP intoxication and repeated daily until sacrifice after MPTP intoxication. C57Bl/6 mice were injected intraperitoneally four times at 2 h intervals with either 20 mg/kg MPTP-HCl or a corresponding volume of saline. Two or seven days after the end of the MPTP intoxication, the animals were killed and their brains were processed for further analysis. Results: Treatment with PNU-282987 resulted in an attenuation of neuroinflammation in the MPTP-lesioned SN. Furthermore, PNU-282987 attenuated MPTP-induced dopaminergic cell loss in the SN and reduced striatal dopamine depletion. Unexpectedly, mecamylamine lowered neuroinflammation as well, though it did not show a neuroprotective potential at the nigral level. Conclusions: Our results demonstrate the therapeutic potential of the selective α7 nicotinic acetylcholine agonist PNU-282987 in attenuating neuroinflammation and toxin-induced loss of dopaminergic neurons in the acute MPTP mouse model of PD. Show more

Keywords: α7 nicotinic acetylcholine receptor, cholinergic anti-inflammatory signalling pathway, PNU-282987, mecamylamine, MPTP, neurodegeneration, neuroinflammation, Parkinson's disease

DOI: 10.3233/JPD-120157

Citation: Journal of Parkinson's Disease, vol. 3, no. 2, pp. 161-172, 2013

Authors: Hammer, Michael J.

Article Type: Research Article

Abstract: Background: Phonatory onset is important for speech and voice and may be substantially impaired in people with Parkinson's Disease (PD). However, the physiologic contributions of laryngeal and respiratory control to phonatory onset in PD are not well understood. Acoustic measurement of phonatory onset in neurological disease has been limited due to the confounding effects of dysarthria and the limited yield of physiologic detail. Objective: The purpose of this study was to test whether air flow measures would be useful to characterize respiratory and laryngeal contributions to phonatory onset, whether acoustic and air flow measures of phonatory onset were aberrant in …PD, and whether deficits were significantly associated with voice severity. Methods: Twenty-one PD participants were tested and compared with 25 healthy controls. Testing included acoustic and air flow measures of phonatory onset during syllable production ([pa]) and measures of voice severity. Results: Air flow assessment was possible for all participants; acoustic assessment was only possible for 86% of PD participants. Air flow and acoustic measures revealed shorter phonatory onset times for PD participants than controls. Air flow measures also revealed that PD participants expelled less lung air volume per syllable. Aberrant timing of phonatory onset and reduced lung air volume were associated with increased voice severity. Conclusions: These findings suggest that air flow measures may be useful to assess the laryngeal and respiratory contributions to phonatory onset. These results also suggest that both respiratory and laryngeal control deficits may contribute to phonatory errors in PD, and that phonatory onset deficits are associated with voice severity. Show more

Keywords: Speech, voice, air flow, volume, acoustic, larynx

DOI: 10.3233/JPD-130180

Citation: Journal of Parkinson's Disease, vol. 3, no. 2, pp. 173-179, 2013

Authors: Disbrow, Elizabeth A. | Sigvardt, Karen A. | Franz, Elizabeth A. | Turner, Robert S. | Russo, Kim A. | Hinkley, Leighton B. | Herron, Timothy J. | Ventura, Maria I. | Zhang, Lin | Malhado-Chang, Norika

Article Type: Research Article

Abstract: Background: Parkinson's disease (PD), traditionally considered a movement disorder, has been shown to affect executive function such as the ability to adapt behavior in response to new environmental situations. Objective: to identify the impact of PD on neural substrates subserving two specific components of normal movement which we refer to as activation (initiating an un-cued response) and inhibition (suppressing a cued response). Methods: We used fMRI to measure pre-movement processes associated with activating an un-cued response and inhibiting a cued response plan in 13 PD (ON anti-parkinsonian medications) and 13 control subjects. Subjects were shown a visual arrow cue followed …by a matched or mismatched response target that instructed them to respond with a right, left, or bilateral button press. In mismatched trials, an un-cued (new) response was initiated, or the previously cued response was suppressed. Results: We were able to isolate pre-movement responses in dorsolateral prefrontal cortex, specifically in the right hemisphere. During the activation of an un-cued movement, PD subjects showed decreased activity in the putamen and increased cortical activity in bilateral DLPFC, SMA, subcentral gyrus and inferior frontal operculum. During inhibition of a previously cued movement, the PD group showed increased activation in SMA, S1/M1, premotor and superior parietal areas. Conclusion: Right DLPFC plays a role in pre-movement processes, and DLPFC activity is abnormal in PD. Decreased specificity of responses was observed in multiple ROI's. The basal ganglia are involved in circuits that coordinate activation and inhibition involved in action selection as well as execution. Show more

Keywords: Executive function, dorsolateral prefrontal cortex, fMRI

DOI: 10.3233/JPD-130181

Citation: Journal of Parkinson's Disease, vol. 3, no. 2, pp. 181-192, 2013

Authors: Gordon, Paul H. | Zhao, Hongwei | Bartley, Denise | Sims, LT James G. | Begay, Mae-Gilene | Pirio Richardson, Sarah | Lewis, Johnnye | Rowland, Andrew S.

Article Type: Research Article

Abstract: Background: The prevalence of Parkinson disease (PD) varies by geographic location and ethnicity, but has never been studied among the Navajo. Methods: Period prevalence was calculated using the number of people diagnosed with PD in the Shiprock Service Unit Indian Health Service database during 1995–1999, 2000–2004, and 2005–2009 as the numerator, and the number seen for any reason as the denominator. Age-standardized rates were calculated using the 2000 US population. Results: During 2005–2009, 126 people were seen with PD (crude prevalence = 203.7/100,000 population). The age-adjusted rate was 335.9 (95% C. I. 277.8–394.0) overall, 438.5 (95% C.I. 336.5–540.5) in men …and 259.7 (95% C.I. 192.8–326.7; p = 0.004) in women. The adjusted rate increased with age: 788.8 (95% C.I. 652.0–925.7) for age 40 and above to 1964.9 (95% C.I. 1613.7–2316.1) for age 60 and above. Adjusted rates were 246.6 (95% C.I. 187.2–306.0) in 1995–1999 and 284.7 (95% C.I. 227.0–342.4) in 2000–2004. Conclusion: Parkinson disease appears common among the Navajo. Estimates increased with age and time, and were higher in men. In-person interviews are needed to confirm these estimates, and to determine incidence, quality of care, and risk factors for PD among the Navajo. Show more

Keywords: Parkinson disease, prevalence, Navajo, Indians, North American, epidemiology, health status disparities

DOI: 10.3233/JPD-120158

Citation: Journal of Parkinson's Disease, vol. 3, no. 2, pp. 193-198, 2013

Authors: Beijer, Tim R. | Lord, Stephen R. | Brodie, Matthew A. D.

Article Type: Research Article

Abstract: In this pilot study, we investigated the validity and reliability of low-cost handheld video camera recordings for measuring gait in people with early stage Parkinson's disease (PD). Five participants with PD, Hoehn & Yahr stage I–II, mean age 66.2 years and five healthy age-matched controls were recruited. Participants walked across a GAITRite® electronic walkway at self-selected pace while video was simultaneously recorded. Data from both systems were analyzed and compared. Step time variability, measured from handheld video recordings, revealed significant (p ≤ 0.05) differences between the gait of early stage PD and controls. Concurrent validity between video analyses and …GAITRite were good (ICC(2,1) ≥ 0.86) for mean step time and mean dual support duration. However, the inter-assessor reliability for the video analysis was poor for step time variability (ICC(2,1) = 0.18). More reliable measurement of step time variability may require a system to measure extended periods of walking. Further research involving longer walks and more participants with higher stages of PD is required to investigate if step time variability can be measured with acceptable reliability using video recordings. If this could be demonstrated, this simple technology could be adapted to run on a tablet or smart phone, providing low cost gait assessments without the need for specialized equipment and expensive infrastructure. Show more

Keywords: Parkinson's disease, gait, gait variability, GAITRite, video

DOI: 10.3233/JPD-130179

Citation: Journal of Parkinson's Disease, vol. 3, no. 2, pp. 199-203, 2013

Authors: Cholerton, Brenna A. | Zabetian, Cyrus P. | Quinn, Joseph F. | Chung, Kathryn A. | Peterson, Amie | Espay, Alberto J. | Revilla, Fredy J. | Devoto, Johnna | Watson, G. Stennis | Hu, Shu-Ching | Edwards, Karen L. | Montine, Thomas J. | Leverenz, James B.

Article Type: Research Article

Abstract: Background: The substantial proportion of individuals with Parkinson's disease (PD) who have or are expected to develop concomitant cognitive impairment emphasizes the need for large, well-characterized participant cohorts to serve as a basis for research into the causes, manifestations, and potential treatments of cognitive decline in those with PD. Objective: To establish a multi-site clinical core that cognitively and clinically characterizes patients with PD by obtaining quality longitudinal clinical, neuropsychological, and validated biomarker data. Methods: Six hundred nineteen participants with idiopathic PD (68.0 ± 9.1 years, 7.1 ± 6.2 years since diagnosis, 70% males) were enrolled in the Pacific Northwest …Udall Center (PANUC), one of the Morris K. Udall Centers of Excellence for Parkinson's Research, Clinical Consortium and underwent comprehensive clinical and neuropsychological assessment. Participants were diagnosed with no cognitive impairment (PD-NCI), mild cognitive impairment (PD-MCI), or dementia (PDD) at a diagnostic consensus conference. Results: A substantial proportion of the overall sample was diagnosed with cognitive impairment at baseline: 22% with PDD and 59% with PD-MCI. A higher rate of cognitive impairment was observed in men than women (87% vs. 68%, p < 0.0001), despite a higher level of education. Most patients older than 50 years at the time of diagnosis and with disease duration greater than 10 years were cognitively impaired or demented. Conclusions: The PANUC Clinical Consortium is a clinically and cognitively well-characterized cohort of patients with PD. Baseline cohort characteristics demonstrate a high rate of cognitive impairment in the sample, as well as potential sex differences with regard to cognitive diagnosis. The PANUC Clinical Consortium, with its access to biomarker, genetic, and autopsy data, provides an excellent foundation for detailed research related to cognitive impairment in PD. Show more

Keywords: Cognition, cohort studies, dementia, mild cognitive impairment, movement disorders, Parkinson disease

DOI: 10.3233/JPD-130189

Citation: Journal of Parkinson's Disease, vol. 3, no. 2, pp. 205-214, 2013

Authors: Rothman, Sarah M. | Griffioen, Kathleen J. | Vranis, Neil | Ladenheim, Bruce | Cong, Wei-na | Cadet, Jean-Lud | Haran, Jamie | Martin, Bronwen | Mattson, Mark P.

Article Type: Research Article

Abstract: Background: Mutations in the human α-synuclein gene lead to early-onset Parkinson's disease (PD); however, phenotypes of α-synuclein mutant mice vary depending upon the promoter driving transgene expression. Objective: The goal of this study was to characterize behavior and neurochemical alterations in mice expressing mutant (A53T) human α-synuclein, controlled by a neuron-specific Thy-1 promoter. Our data provide important additional phenotypic and biochemical characterization of a previously generated model of PD. Methods: A53T (SNCA) and wild type (WT) littermate mice were evaluated for motor function (rotarod and stride length) and anxiety (elevated plus maze and open field) every 2 weeks. At 24 …weeks mice were evaluated in a Comprehensive Lab Animal Monitoring System (CLAMS). A separate cohort of mice were euthanized at 12, 24 and 36 weeks for immunoblot analysis of α-synuclein, dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the striatum, and hypothalamic serotonin and metabolites were measured. Results: SNCA mice display significant motor deficits at 14–18 weeks of age compared to WT mice, which progress over time. CLAMS analysis revealed an increase in activity during the dark phase and a reduction in overall estimated sleep time for SNCA mice compared to WT consistent with clinical reports of sleep abnormalities in PD. A transient change in the levels of DAT appeared at 12 weeks in the striatum and serotonin levels were also altered in the hypothalamus at this time point. Conclusions: This PD model displays consistent and clinically relevant motor and sleep phenotypes. Anxiety phenotypes are consistent with other α-synuclein based PD models yet incongruous with typical clinical symptoms. Early increases in serotonin levels potentially explain reductions in anxiety behaviors and sleep. Show more

Keywords: Parkinson's disease, α-synuclein, hypothalamus, dopamine, circadian, stride length, anxiety, sleep, serotonin

DOI: 10.3233/JPD-120130

Citation: Journal of Parkinson's Disease, vol. 3, no. 2, pp. 215-229, 2013