Journal of Parkinson's Disease - Volume 3, issue 1

Authors: Jenner, Peter | Morris, Huw R. | Robbins, Trevor W. | Goedert, Michel | Hardy, John | Ben-Shlomo, Yoav | Bolam, Paul | Burn, David | Hindle, John V. | Brooks, David | For The Parkinson's UK Discussion Group

Article Type: Review Article

Abstract: The definition of Parkinson's disease (PD) is changing with the expansion of clinical phenomenology and improved understanding of environmental and genetic influences that impact on the pathogenesis of the disease at the cellular and molecular level. This had led to debate and discussion with as yet, no general acceptance of the direction that change should take either at the level of diagnosis or of what should and should not be sheltered under an umbrella of PD. This article is one contribution to this on-going discussion. There are two different themes running through the article - widening the definition of PD/LBD/synucleinopathies …and the heterogeneity that exists within PD itself from a clinical, pathological and genetic perspective. The conclusion reached is that in the future, further diagnostic categories will need to be recognized. These are likely to include - Parkinson's syndrome, Parkinson's syndrome likely to be Lewy body PD, clinical PD (defined by QSBB criteria), Lewy body disease (PD, LBD, REM SBD) and synucleinopathies (including LBD, MSA). Show more

Keywords: Parkinson's disease, phenomenology, aetiology, pathology, pathogenesis, synucleinopathies

DOI: 10.3233/JPD-130175

Citation: Journal of Parkinson's Disease, vol. 3, no. 1, pp. 1-11, 2013

Authors: Decressac, Mickael | Björklund, Anders

Article Type: Short Communication

Abstract: The development of dyskinesia upon chronic L-DOPA treatment is a major complication for the management of the motor symptoms in Parkinson's disease (PD) patients. Efforts are made to understand the underlying mechanisms and identify targets for the pharmacological alleviation of dyskinesia without affecting the therapeutic effect of L-DOPA. Previous studies have shown that the mTOR pathway is hyperactive in dyskinesia as a consequence of D1 receptor hypersensitivity. We investigated the effect of the FDA-approved mTOR inhibitor Temsirolimus (CCI-779), currently used in the clinic, on the development of LID and on the severity of already established LID in hemi-parkinsonian rats. Systemic …delivery of CCI-779 prevented the development of LID and significantly alleviated the severity of dyskinesia in L-DOPA-primed animals. This was associated with a reduced activation of the mTOR pathway in striatal medium spiny neurons. Drugs with mTOR inhibiting activity that are actively developed in cancer research may be of interest for the management of LID in PD patients. Show more

Keywords: mTOR inhibition, dyskinesia, Parkinson's disease

DOI: 10.3233/JPD-120155

Citation: Journal of Parkinson's Disease, vol. 3, no. 1, pp. 13-17, 2013

Authors: Karlsson, Magdalena Kauczynska | Sharma, Praveen | Aasly, Jan | Toft, Mathias | Skogar, Örjan | Sæbø, Solve | Lönneborg, Anders

Article Type: Research Article

Abstract: Background: A blood-based test for the early detection of Parkinson's disease (PD) would be an important diagnostic tool and useful for patient selection when developing novel drugs or treatments for the disease. Objective: Here, we aimed to identify potential biomarkers associated with PD. Methods: We applied gene expression profiling to the study of peripheral blood from 75 healthy control subjects and 79 PD patients at different stages of the disease. Healthy control subjects were matched for age and gender with PD subjects, and the diagnosis of patients was based on clinical evaluation by specialists in movement disorders. RNA was extracted …from the blood samples and the gene expressions were measured using the Illumina HumanHT-12 v4.0 Expression BeadChip. Results: Our results support previous studies that gene expression in blood may be instrumental in the search for molecular biomarkers for PD. Single cross-validation results show that PD can be correctly classified from healthy controls with an agreement of 88% to clinical diagnosis. De novo PD patients are classified with a sensitivity of 87%, which is close to what was achieved for the patients having a confirmed PD diagnosis with disease duration <5 and >5 years (93% and 88%). A double cross-validation procedure showed that using a selected set of around 650 informative genes, similar results are achieved. Functional analysis of the selected genes showed genes significantly associated to mitochondrial dysfunction, protein ubiquitination, gene expression and cell death. Conclusions: PD affects gene expression in blood, suggesting the potential for the development of a blood-based gene expression test. Show more

Keywords: Parkinson's disease, biomarker, blood, classification, gene expression

DOI: 10.3233/JPD-120159

Citation: Journal of Parkinson's Disease, vol. 3, no. 1, pp. 19-29, 2013

Authors: Grosset, Katherine A. | Malek, Naveed | Morgan, Frazer | Grosset, Donald G.

Article Type: Research Article

Abstract: Background: In later stages of Parkinson's disease, treatment of ‘off’ periods with subcutaneous apomorphine is helpful but requires injection; inhaled apomorphine would be potentially more convenient. Objectives: To identify optimal efficacy, safety and tolerability for inhaled apomorphine in reversing Parkinson's disease ‘off’ periods. Methods: A randomized, double-blind, 2:1 active:placebo, parallel-group, ascending dose titration study was conducted at 16 centres in 3 countries. Inhaled apomorphine was administered under observation, at escalating fine particle doses of 1.5, 2.5, 3.5 and 4.5 mg. This was followed by at-home patient self-treatment for 2 to 4 weeks, assessed from ‘on-off’ diaries. Results: In 55 patients, …mean age 65.6 years (range 47–79), mean disease duration 12 years (range 5–22), the mean improvement in the unified PD rating scale part 3 (UPDRS 3) was significantly greater for apomorphine (mean dose 2.3 mg) at 19.5 (standard deviation 13.6) than for placebo at 9.9 (9.6), least squares mean difference 8.4 (95% confidence interval 1.2 to 15.5, p = 0.023). During at-home testing, mean ‘off’ time per day was reduced by 139.8 minutes (standard deviation 149.6) for apomorphine versus 68.0 (108.6) minutes for placebo, least squares mean difference not significant at 100.5 minutes (95% confidence interval −12.0 to 212.9, p = 0.078). The onset of action was faster for apomorphine (mean 8.1 SD 6.2 minutes) than placebo (mean 13.1 SD 6.6 minutes) (p < 0.0001). Reversal of ‘off’ episodes was significantly more likely for episodes treated with apomorphine than those treated with placebo: apomorphine 64.6% SD 32.3 of episodes versus placebo 11.1% SD 15.3 (p < 0.0001). During at-home treatment, 36% of apomorphine and 20% of placebo patients experienced adverse events. Conclusions: Inhaled apomorphine in the dose range 1.5 to 4.5 mg, significantly improved UPDRS 3 scores in the clinic, and aborted a greater proportion of ‘off’ periods at-home, compared to placebo. However, daily ‘off’ time was not significantly reduced by the use of inhaled apomorphine. Show more

Keywords: Parkinson's disease, apomorphine, fluctuations

DOI: 10.3233/JPD-120142

Citation: Journal of Parkinson's Disease, vol. 3, no. 1, pp. 31-37, 2013

Authors: Hammer, Michael J. | Murphy, Caitlin A. | Abrams, Trisha M.

Article Type: Research Article

Abstract: Background: Individuals with Parkinson's disease (PD) often experience substantial impairment of swallow control, and are typically unaware of the presence or severity of their impairments suggesting that these individuals may also experience airway sensory deficits. However, the degree to which impaired swallow function in PD may relate to airway sensory deficits has yet to be formally tested. Objective: The purpose of this study was to examine whether airway sensory function is associated with swallow impairment in PD. Methods: Eighteen PD participants and 18 healthy controls participated in this study and underwent endoscopic assessment of airway somatosensory function, endoscopic assessment of …swallow function, and clinical ratings of swallow and disease severity. Results: PD participants exhibited abnormal airway somatosensory function and greater swallow impairment compared with healthy controls. Swallow and sensory deficits in PD were correlated with disease severity. Moreover, PD participants reported similar self-rated swallow function as healthy controls, and swallow deficits were correlated with sensory function suggesting an association between impaired sensory function and poor self-awareness of swallow deficits in PD. Conclusions: These results suggest that control of swallow is influenced by airway somatosensory function, that swallow-related deficits in PD are related to abnormal somatosensation, and that swallow and airway sensory function may degrade as a function of disease severity. Therefore, the basal ganglia and related neural networks may play an important role to integrate airway sensory input for swallow-related motor control. Furthermore, the airway deficits observed in PD suggest a disintegration of swallow-related sensory and motor control. Show more

Keywords: Swallow, aspiration, penetration, residue, protection, larynx, non-motor

DOI: 10.3233/JPD-120161

Citation: Journal of Parkinson's Disease, vol. 3, no. 1, pp. 39-44, 2013

Authors: Whitworth, Stephanie R. | Loftus, Andrea M. | Skinner, Timothy C. | Gasson, Natalie | Barker, Roger A. | Bucks, Romola S. | Thomas, Meghan G.

Article Type: Research Article

Abstract: BACKGROUND: Personality traits influence health-related quality of life (HRQoL) in Parkinson's disease (PD). Further, an individual's personality traits can influence the strategies they use to cope with a particular stressful situation. However, in PD, the interplay between personality traits, choice of coping strategy, and their subsequent effect on HRQoL remains unclear. OBJECTIVE: The objective of this study was to examine whether personality (neuroticism and extraversion) indirectly affects HRQoL through the use of specific psychological coping strategies. METHODS: One hundred and forty-six patients with PD completed questionnaires on personality (Big Five Aspects Scale; BFAS), coping (Ways of Coping Questionnaire; WCQ), and …mood-specific (Depression, Anxiety and Stress Scale; DASS-21) and disease-specific HRQoL (Parkinson's Disease Questionnaire; PDQ-39). RESULTS: After controlling for gender, age at diagnosis, and age at testing, the emotion-focused coping strategy of escape-avoidance was significantly correlated with neuroticism and certain aspects of HRQoL (cognitive impairment and social support). This suggests that neurotic personality traits may negatively impact on some aspects of HRQoL due to an increased use of escape-avoidance coping strategies. By contrast, planned problem-solving and escape-avoidance coping strategies were both significantly linked to extraversion and interpersonal and mood-related domains of HRQoL. This suggests that extraversion may positively impact on some aspects of HRQoL due to patients adopting greater planned, problem-solving coping strategies, and using fewer escape-avoidance coping mechanisms. CONCLUSIONS: Psychological interventions aimed at targeting maladaptive coping strategies, such as the use of escape-avoidance coping, may be effective in minimising the negative impact of neuroticism on HRQoL in PD. Show more

Keywords: Parkinson disease, coping skills, personality, extraversion (psychology), quality of life

DOI: 10.3233/JPD-120149

Citation: Journal of Parkinson's Disease, vol. 3, no. 1, pp. 45-53, 2013

Authors: Hirsch, Elaina S. | Adler, Geri | Amspoker, Amber B. | Williams, James R. | Marsh, Laura

Article Type: Research Article

Abstract: Background: Under-recognition of psychiatric disturbances in patients with Parkinson's disease (PD) contributes to greater overall morbidity. Little is known about the value of collateral psychiatric history, obtained using standardized assessments with informants, for increasing recognition of PD-related psychiatric illness. Objective: To examine the extent to which informants provide critical information that enabled psychiatrists to establish psychiatric diagnoses in patients with PD. Methods: Individuals with PD (n = 223) and an informant were interviewed separately regarding the PD patient's psychiatric history and current status. A six-psychiatrist panel rated the extent to which informant data was required to establish the final consensus …best-estimate current psychiatric diagnoses. Informants rated as “Crucial” or “Significantly Informative” comprised a “Critical Informant” (CI) subgroup; remaining informants were classified as the “Non-Critical Informant” (NCI) subgroup. Results: Of the informants, 71 (31.4%) were “critical” for determining a psychiatric diagnosis. Without a CI, 81.3% of those with impulse control disorders and 43.8% of those with anxiety disorders would not have been diagnosed. Male PD patients and those with less severe motor deficits were also more likely to require a CI. Conclusions: Informants aid in the identification of psychiatric diagnoses, especially impulse control and anxiety disorders. This has implications for clinical practice and conduction of clinical trials. Show more

Keywords: Parkinson's disease, informant, psychiatric disorder, depression, caregiver

DOI: 10.3233/JPD-120170

Citation: Journal of Parkinson's Disease, vol. 3, no. 1, pp. 55-60, 2013

Authors: Lawson, Rachael A. | Millar, David | Brown, Richard G. | Burn, David J.

Article Type: Research Article

Abstract: Background: Anxiety disorder and anxiety symptomatology are common in Parkinson's disease (PD), with up to 25% patients experiencing significant worry. There is no systematic evidence base for the management of anxiety or anxiety related symptoms such as worry in PD. Objectives: To investigate whether cognitive therapy, delivered as bibliotherapy, is an effective intervention for worry in PD. Methods: 54 participants were randomly allocated to a guided reading group and a control group. The guided reading group were given a CBT based self-help resource called What? Me Worry!?! to work through over eight weeks, with telephone support at two week intervals. …Controls were given information about worry only, and one phone call. Measures of worry, intolerance of uncertainty, metacognitions and health status were taken at baseline and after 3 months. Results: Analysable data were obtained for 15 controls and 17 from the guided reading group. Worry and intolerance of uncertainty were significantly reduced in the guided reading group. However, no significant differences were found for the follow up measures between the groups. Conclusions: Bibliotherapy has the potential to be useful and cost effective as a management strategy for the treatment of worry in people with PD. Show more

Keywords: Parkinson's disease, anxiety, cognitive behaviour therapy, bibliotherapy

DOI: 10.3233/JPD-120156

Citation: Journal of Parkinson's Disease, vol. 3, no. 1, pp. 61-68, 2013

Authors: Hwang, Kristy S. | Beyer, Mona K. | Green, Amity E. | Chung, Christine | Thompson, Paul M. | Janvin, Carmen | Larsen, Jan P. | Aarsland, Dag | Apostolova, Liana G.

Article Type: Research Article

Abstract: Background: Cognitive impairment is very common in patients with Parkinson's disease (PD). Brain changes accompanying cognitive decline in PD are still not fully established. Methods: We applied cortical pattern matching and cortical thickness analyses to the three-dimensional T1-weighted brain MRI scans of 14 age-matched cognitively normal elderly (NC), 12 cognitively normal PD (PDC), and 11 PD dementia (PDD) subjects. We used linear regression models to investigate the effect of diagnosis on cortical thickness. All maps were adjusted for multiple comparisons using permutation testing with a threshold p < 0.01. Results: PDD showed significantly thinner bilateral sensorimotor, perisylvian, lateral parietal, as …well as right posterior cingulate, parieto-occipital, inferior temporal and lateral frontal cortices relative to NC (left pcorrected = 0.06, right pcorrected = 0.009). PDD showed significantly thinner bilateral sensorimotor, right frontal and right parietal-occipital cortices relative to PDC (right pcorrected = 0.05). The absolute difference in cortical thickness between PDD and the other diagnostic groups ranged from 3% to 19%. Conclusion: Our data shows that cognitive decline in PD is associated with cortical atrophy. PDD subjects have the most widespread gray matter atrophy suggesting more cortical involvement as PD patients progress to dementia. Show more

Keywords: Parkinson's disease, dementia, magnetic resonance imaging, MRI, brain atrophy, cortical atrophy, gray matter atrophy

DOI: 10.3233/JPD-120151

Citation: Journal of Parkinson's Disease, vol. 3, no. 1, pp. 69-76, 2013

Authors: Purushothuman, Sivaraman | Nandasena, Charith | Peoples, Cassandra L. | El Massri, Nabil | Johnstone, Daniel M. | Mitrofanis, John | Stone, Jonathan

Article Type: Research Article

Abstract: Background: There is growing evidence that the spice saffron, which contains powerful anti-oxidants, offers protection against neurodegenerative disorders, including age-related macular degeneration and Alzheimer's disease. Objective: We examined whether saffron pre-treatment protects dopaminergic cells of the substantia nigra pars compacta (SNc) and retina in an acute MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease. Methods: BALB/c mice received MPTP or saline injections over a 30 hour period, followed by six days survival. For five days prior to injections, the drinking water of the saffron groups was supplemented with saffron (0.01% w/v), while non-saffron groups received normal tap water. After the survival …period was complete, brains were processed for tyrosine hydroxylase (TH) immunochemistry and the number of TH+ cells was analysed using the optical fractionator method. Results: In both the SNc and retina, non-conditioned MPTP-injected mice had a reduced number of TH+ cells (30–35%) compared to the saline-injected controls. Saffron pre-conditioning mitigated the reduction, with pre-conditioned MPTP-injected mice having SNc and retinal TH+ cell numbers close to control levels, significantly (25–35%) higher than in non-conditioned MPTP-injected mice. Conclusions: Our results indicated that saffron pre-treatment of mice saved many dopaminergic cells of the SNc and retina from parkinsonian (MPTP) insult. Show more

Keywords: Tyrosine hydroxylase, substantia nigra, amacrine cell, neuroprotection, Parkinson's disease

DOI: 10.3233/JPD-130173

Citation: Journal of Parkinson's Disease, vol. 3, no. 1, pp. 77-83, 2013