Autonomic disorders in Parkinson's disease: Estudio del sistema nervioso vegetativo como marcador de sinucleinpatías

140 p.

The epigenome as a therapeutic target for Parkinson's disease

Parkinson’s disease (PD) is a common, progressive neurodegenerative disease characterised by degeneration of nigrostriatal dopaminergic neurons, aggregation of α-synuclein and motor symptoms. Current dopamine-replacement strategies provide symptomatic relief, however their effectiveness wear off over time and their prolonged use leads to disabling side-effects in PD patients. There is therefore a critical need to develop new drugs and drug targets to protect dopaminergic neurons and their axons from degeneration in PD. Over recent years, there has been robust evidence generated showing that epigenetic dysregulation occurs in PD patients, and that epigenetic modulation is a promising therapeutic approach for PD. This article first discusses the present evidence implicating global, and dopaminergic neuron-specific, alterations in the methylome in PD, and the therapeutic potential of pharmacologically targeting the methylome. It then focuses on another mechanism of epigenetic regulation, histone acetylation, and describes how the histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes that mediate this process are attractive therapeutic targets for PD. It discusses the use of activators and/or inhibitors of HDACs and HATs in models of PD, and how these approaches for the selective modulation of histone acetylation elicit neuroprotective effects. Finally, it outlines the potential of employing small molecule epigenetic modulators as neuroprotective therapies for PD, and the future research that will be required to determine and realise this therapeutic potential.

Probabilistic subgroup identification using Bayesian finite mixture modelling : a case study in Parkinson’s disease phenotype identification

This article explores the use of probabilistic classification, namely finite mixture modelling, for identification of complex disease phenotypes, given cross-sectional data. In particular, if focuses on posterior probabilities of subgroup membership, a standard output of finite mixture modelling, and how the quantification of uncertainty in these probabilities can lead to more detailed analyses. Using a Bayesian approach, we describe two practical uses of this uncertainty: (i) as a means of describing a person’s membership to a single or multiple latent subgroups and (ii) as a means of describing identified subgroups by patient-centred covariates not included in model estimation. These proposed uses are demonstrated on a case study in Parkinson’s disease (PD), where latent subgroups are identified using multiple symptoms from the Unified Parkinson’s Disease Rating Scale (UPDRS).

A randomised controlled trial of an enhanced interdisciplinary community based group program for people with Parkinson’s disease: study rationale and protocol

Parkinson’s disease (PD) is a progressive, chronic neurodegenerative disorder for which there is no known cure. Physical exercise programs may be used to assist with the physical management of PD. Several studies have demonstrated that community based physical therapy programs are effective in reducing physical aspects of disability among people with PD. While multidisciplinary therapy interventions may have the potential to reduce disability and improve the quality of life of people with PD, there is very limited clinical trial evidence to support or refute the use of a community based multidisciplinary or interdisciplinary programs for people with PD. A two group randomized trial is being undertaken within a community rehabilitation service in Brisbane, Australia. Community dwelling adults with a diagnosis of Idiopathic Parkinson’s disease are being recruited. Eligible participants are randomly allocated to a standard exercise rehabilitation group program or an intervention group which incorporates physical, cognitive and speech activities in a multi-tasking framework. Outcomes will be measured at 6-week intervals for a period of six months. Primary outcome measures are the Montreal Cognitive Assessment (MoCA) and the Timed Up and Go (TUG) cognitive test. Secondary outcomes include changes in health related quality of life, communication, social participation, mobility, strength and balance, and carer burden measures. This study will determine the immediate and long-term effectiveness of a unique multifocal, interdisciplinary, dual-tasking approach to the management of PD as compared to an exercise only program. We anticipate that the results of this study will have implications for the development of cost effective evidence based best practice for the treatment of people with PD living in the community.

Diabetes foot disease : the Cinderella of Australian diabetes management?

Diabetes is one of the greatest public health challenges to face Australia. It is already Australia’s leading cause of kidney failure, blindness (in those under 60 years) and lower limb amputation, and causes significant cardiovascular disease. Australia’s diabetes amputation rate is one of the worst in the developed world, and appears to have significantly increased in the last decade, whereas some other diabetes complication rates appear to have decreased. This paper aims to compare the national burden of disease for the four major diabetes-related complications and the availability of government funding to combat these complications, in order to determine where diabetes foot disease ranks in Australia. Our review of relevant national literature indicates foot disease ranks second overall in burden of disease and last in evidenced-based government funding to combat these diabetes complications. This suggests public funding to address foot disease in Australia is disproportionately low when compared to funding dedicated to other diabetes complications. There is ample evidence that appropriate government funding of evidence-based care improves all diabetes complication outcomes and reduces overall costs. Numerous diverse Australian peak bodies have now recommended similar diabetes foot evidence-based strategies that have reduced diabetes amputation rates and associated costs in other developed nations. It would seem intuitive that “it’s time” to fund these evidence-based strategies for diabetes foot disease in Australia as well.

Risk factors for malnutrition in community-dwelling people with Parkinson’s disease

In the elderly, the risks for protein-energy malnutrition from older age, dementia, depression and living alone have been well-documented. Other risk factors including anorexia, gastrointestinal dysfunction, loss of olfactory and taste senses and early satiety have also been suggested to contribute to poor nutritional status. In Parkinson’s disease (PD), it has been suggested that the disease symptoms may predispose people with PD to malnutrition. However, the risks for malnutrition in this population are not well-understood. The current study’s aim was to determine malnutrition risk factors in community-dwelling adults with PD. Nutritional status was assessed using the Patient-Generated Subjective Global Assessment (PG-SGA). Data about age, time since diagnosis, medications and living situation were collected. Levodopa equivalent doses (LDED) and LDED per kg body weight (mg/kg) were calculated. Depression and anxiety were measured using the Beck’s Depression Inventory (BDI) and Spielberger Trait Anxiety questionnaire, respectively. Cognitive function was assessed using the Addenbrooke’s Cognitive Examination (ACE-R). Non-motor symptoms were assessed using the Scales for Outcomes in Parkinson's disease-Autonomic (SCOPA-AUT) and Modified Constipation Assessment Scale (MCAS). A total of 125 community-dwelling people with PD were included, average age of 70.2±9.3(35-92) years and average time since diagnosis of 7.3±5.9(0–31) years. Average body mass index (BMI) was 26.0±5.5kg/m2. Of these, 15% (n=19) were malnourished (SGA-B). Multivariate logistic regression analysis revealed that older age (OR=1.16, CI=1.02-1.31), more depressive symptoms (OR=1.26, CI=1.07-1.48), lower levels of anxiety (OR=.90, CI=.82-.99), and higher LDED per kg body weight (OR=1.57, CI=1.14-2.15) significantly increased malnutrition risk. Cognitive function, living situation, number of prescription medications, LDED, years since diagnosis and the severity of non-motor symptoms did not significantly influence malnutrition risk. Malnutrition results in poorer health outcomes. Proactively addressing the risk factors can help prevent declines in nutritional status. In the current study, older people with PD with depression and greater amounts of levodopa per body weight were at increased malnutrition risk.

Effects of textured insoles on balance in people with Parkinson’s Disease

Background Degradation of the somatosensory system has been implicated in postural instability and increased falls risk for older people and Parkinson’s disease (PD) patients. Here we demonstrate that textured insoles provide a passive intervention that is an inexpensive and accessible means to enhance the somatosensory input from the plantar surface of the feet. Methods 20 healthy older adults (controls) and 20 participants with PD were recruited for the study. We evaluated effects of manipulating somatosensory information from the plantar surface of the feet using textured insoles. Participants performed standing tests, on two different surfaces (firm and foam), under three footwear conditions: 1) barefoot; 2) smooth insoles; and 3) textured insoles. Standing balance was evaluated using a force plate yielding data on the range of anterior-posterior and medial-lateral sway, as well as standard deviations for anterior-posterior and medial-lateral sway. Results On the firm surface with eyes open both the smooth and textured insoles reduced medial-lateral sway in the PD group to a similar level as the controls. Only the textured insole decreased medial-lateral sway and medial-lateral sway standard deviation in the PD group on both surfaces, with and without visual input. Greatest benefits were observed in the PD group while wearing the textured insoles, and when standing on the foam surface with eyes closed. Conclusions Data suggested that textured insoles may provide a low-cost means of improving postural stability in high falls-risk groups, such as people with PD.

Executive function and postural instability in people with Parkinson’s disease

The specific aspects of cognition contributing to balance and gait have not been clarified in people with Parkinson’s disease (PD). Twenty PD participants and twenty age- and gender-matched healthy controls were assessed on cognition and clinical mobility tests. General cognition was assessed with the Mini Mental State Exam and the Addenbrooke’s Cognitive Exam. Executive function was evaluated using the Trail Making Tests (TMT-A and TMT-B) and a computerized cognitive battery which included a series of choice reaction time (CRT) tests. Clinical gait and balance measures included the Tinetti, Timed Up & Go, Berg Balance and Functional Reach tests. PD participants performed significantly worse than the controls on the tests of cognitive and executive function, balance and gait. PD participants took longer on Trail Making Tests, CRT-Location and CRT-Colour (inhibition response). Furthermore, executive function, particularly longer times on CRT-Distracter and greater errors on the TMT-B were associated with worse balance and gait performance in the PD group. Measures of general cognition were not associated with balance and gait measures in either group. For PD participants, attention and executive function were impaired. Components of executive function, particularly those involving inhibition response and distracters, were associated with poorer balance and gait performance in PD.

Improved nutritional status is related to improved quality of life in Parkinson’s disease

Background: Quality of life is poorer in Parkinson’s disease than in other conditions and in the general population without Parkinson’s disease. Malnutrition also results in poorer quality of life. This study aimed at determining the relationship between quality of life and nutritional status. Methods: Community-dwelling people with Parkinson’s disease >18 years old were recruited. The Patient-Generated Subjective Global Assessment (PG-SGA) assessed nutritional status. The Parkinson’s Disease Questionnaire 39 (PDQ-39) measured quality of life. Phase I was cross-sectional. The malnourished in Phase I were eligible for a nutrition intervention phase, randomised into 2 groups: standard care (SC) with provision of nutrition education materials only and intervention (INT) with individualised dietetic advice and regular weekly follow-up. Data were collected at baseline, 6 weeks, and 12 weeks. Results: Phase I consisted of 120 people who completed the PDQ-39. Phase II consisted of 9 in the SC group and 10 in the INT group. In Phase I, quality of life was poorer in the malnourished, particularly for mobility and activities of daily living domains. There was a significant correlation between PG-SGA and PDQ-39 scores (Phase I, rs = 0.445, p = .000; Phase II, rs = .426, p = .002). In Phase II, no significant difference in the PDQ-39 total or sub-scores was observed between the INT and SC groups; however, there was significant improvement in the emotional well-being domain for the entire group, X2(2) = 8.84, p = .012. Conclusions: Malnourished people with Parkinson’s disease had poorer quality of life than the well-nourished, and improvements in nutritional status resulted in quality of life improvements. Attention to nutritional status is an important component of quality of life and therefore the total care of people with Parkinson’s disease.

The management of venereal disease in New South Wales, 1871 to 1916

Practical techniques to manage the dangers associated with sexually transmitted diseases have varied considerably both cross culturally and historically. Adopting a Foucauldian perspective, this article examines sociohistorical aspects of the governance of venereal disease in New South Wales between 1871 and 1916. Public debates and official documents are analysed to identify strategic shifts in practices associated with venereal disease management , especially in relation to prostitution. Particular attention is paid to the development of contagious disease legislation and its role in the regulation of venereal disease . It is argued that during the period in question, two distinct governmental regimes of disease control can be identified. In the first, medical policing managed venereal disease through the mobilisation of repressive controls, requiring the isolation and detention of polluting bodies. In the second, liberal governance adopted pedagogic practices to train populations perceived as either healthy or unhealthy. It is further argued that as liberal strategies of governance came to dominate the management of venereal disease , the association of prostitution with venereal disease began to weaken. Instead, authorities became increasingly concerned with populations whose behaviour was not traditionally linked with venereal disease , such as the young and the sexually inexperienced.

Effects of resistance training on measures of muscular strength in people with Parkinson’s disease: A systematic review and meta-analysis

Objective The aim of this systematic review and meta-analysis was to determine the overall effect of resistance training (RT) on measures of muscular strength in people with Parkinson’s disease (PD). Methods Controlled trials with parallel-group-design were identified from computerized literature searching and citation tracking performed until August 2014. Two reviewers independently screened for eligibility and assessed the quality of the studies using the Cochrane risk-of-bias-tool. For each study, mean differences (MD) or standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for continuous outcomes based on between-group comparisons using post-intervention data. Subgroup analysis was conducted based on differences in study design. Results Nine studies met the inclusion criteria; all had a moderate to high risk of bias. Pooled data showed that knee extension, knee flexion and leg press strength were significantly greater in PD patients who undertook RT compared to control groups with or without interventions. Subgroups were: RT vs. control-without-intervention, RT vs. control-with-intervention, RT-with-other-form-of-exercise vs. control-without-intervention, RT-with-other-form-of-exercise vs. control-with-intervention. Pooled subgroup analysis showed that RT combined with aerobic/balance/stretching exercise resulted in significantly greater knee extension, knee flexion and leg press strength compared with no-intervention. Compared to treadmill or balance exercise it resulted in greater knee flexion, but not knee extension or leg press strength. RT alone resulted in greater knee extension and flexion strength compared to stretching, but not in greater leg press strength compared to no-intervention. Discussion Overall, the current evidence suggests that exercise interventions that contain RT may be effective in improving muscular strength in people with PD compared with no exercise. However, depending on muscle group and/or training dose, RT may not be superior to other exercise types. Interventions which combine RT with other exercise may be most effective. Findings should be interpreted with caution due to the relatively high risk of bias of most studies.

Role of enhanced vector transmission of a new West Nile virus strain in an outbreak of equine disease in Australia in 2011

Background In 2011, a variant of West Nile virus Kunjin strain (WNVKUN) caused an unprecedented epidemic of neurological disease in horses in southeast Australia, resulting in almost 1,000 cases and a 9% fatality rate. We investigated whether increased fitness of the virus in the primary vector, Culex annulirostris, and another potential vector, Culex australicus, contributed to the widespread nature of the outbreak. Methods Mosquitoes were exposed to infectious blood meals containing either the virus strain responsible for the outbreak, designated WNVKUN2011, or WNVKUN2009, a strain of low virulence that is typical of historical strains of this virus. WNVKUN infection in mosquito samples was detected using a fixed cell culture enzyme immunoassay and a WNVKUN- specific monoclonal antibody. Probit analysis was used to determine mosquito susceptibility to infection. Infection, dissemination and transmission rates for selected days post-exposure were compared using Fisher’s exact test. Virus titers in bodies and saliva expectorates were compared using t-tests. Results There were few significant differences between the two virus strains in the susceptibility of Cx. annulirostris to infection, the kinetics of virus replication and the ability of this mosquito species to transmit either strain. Both strains were transmitted by Cx. annulirostris for the first time on day 5 post-exposure. The highest transmission rates (proportion of mosquitoes with virus detected in saliva) observed were 68% for WNVKUN2011 on day 12 and 72% for WNVKUN2009 on day 14. On days 12 and 14 post-exposure, significantly more WNVKUN2011 than WNVKUN2009 was expectorated by infected mosquitoes. Infection, dissemination and transmission rates of the two strains were not significantly different in Culex australicus. However, transmission rates and the amount of virus expectorated were significantly lower in Cx. australicus than Cx. annulirostris. Conclusions The higher amount of WNVKUN2011 expectorated by infected mosquitoes may be an indication that this virus strain is transmitted more efficiently by Cx. annulirostris compared to other WNVKUN strains. Combined with other factors, such as a convergence of abundant mosquito and wading bird populations, and mammalian and avian feeding behaviour by Cx. annulirostris, this may have contributed to the scale of the 2011 equine epidemic.

Black Sigatoka disease: new technologies to strengthen eradication strategies in Australia

In 2001, an incursion of Mycosphaerella fijiensis, the causal agent of black Sigatoka, was detected in Australia's largest commercial banana growing region, the Tully Banana Production Area in North Queensland. An intensive surveillance and eradication campaign was undertaken which resulted in the reinstatement of the disease-free status for black Sigatoka in 2005. This was the first time black Sigatoka had ever been eradicated from commercial plantations. The success of the eradication campaign was testament to good working relationships between scientists, growers, crop monitors, quarantine regulatory bodies and industry. A key contributing factor to the success was the deployment of a PCR-based molecular diagnostic assay, developed by the Cooperative Research Centre for Tropical Plant Protection (CRCTPP). This assay complemented morphological identification and allowed high throughput diagnosis of samples facilitating rapid decision-making during the eradication campaign. This paper describes the development and successful deployment of molecular diagnostics for black Sigatoka. Shortcomings in the gel-based assay are discussed and the advantages of highly specific real-time PCR assays, capable of differentiating between Mycosphaerella fijiensis, Mycosphaerella musicola and Mycosphaerella eumusae are outlined. Real-time assays may provide a powerful diagnostic tool for applications in surveillance, disease forecasting and resistance testing for Sigatoka leaf spot diseases.

Mitochondrial helicase Twinkle in mtDNA copy number regulation and a late-onset disease model

Mitochondrial diseases are caused by disturbances of the energy metabolism. The disorders range from severe childhood neurological diseases to muscle diseases of adults. Recently, mitochondrial dysfunction has also been found in Parkinson s disease, diabetes, certain types of cancer and premature aging. Mitochondria are the power plants of the cell but they also participate in the regulation of cell growth, signaling and cell death. Mitochondria have their own genetic material, mtDNA, which contains the genetic instructions for cellular respiration. Single cell may host thousands of mitochondria and several mtDNA molecules may reside inside single mitochondrion. All proteins needed for mtDNA maintenance are, however, encoded by the nuclear genome, and therefore, mutations of the corresponding genes can also cause mitochondrial disease. We have here studied the function of mitochondrial helicase Twinkle. Our research group has previously identified nuclear Twinkle gene mutations underlying an inherited adult-onset disorder, progressive external ophthalmoplegia (PEO). Characteristic for the PEO disease is the accumulation of multiple mtDNA deletions in tissues such as the muscle and brain. In this study, we have shown that Twinkle helicase is essential for mtDNA maintenance and that it is capable of regulating mtDNA copy number. Our results support the role of Twinkle as the mtDNA replication helicase. No cure is available for mitochondrial disease. Good disease models are needed for studies of the cause of disease and its progression and for treatment trials. Such disease model, which replicates the key features of the PEO disease, has been generated in this study. The model allows for careful inspection of how Twinkle mutations lead to mtDNA deletions and further causes the PEO disease. This model will be utilized in a range of studies addressing the delay of the disease onset and progression and in subsequent treatment trials. In conclusion, in this thesis fundamental knowledge of the function of the mitochondrial helicase Twinkle was gained. In addition, the first model for adult-onset mitochondrial disease was generated.