Rotenone Susceptibility Phenotype in Olfactory Derived Patient Cells as a Model of Idiopathic Parkinson's Disease.

Parkinson's disease is a complex age-related neurodegenerative disorder. Approximately 90% of Parkinson's disease cases are idiopathic, of unknown origin. The aetiology of Parkinson's disease is not fully understood but increasing evidence implies a failure in fundamental cellular processes including mitochondrial dysfunction and increased oxidative stress. To dissect the cellular events underlying idiopathic Parkinson's disease, we use primary cell lines established from the olfactory mucosa of Parkinson's disease patients. Previous metabolic and transcriptomic analyses identified deficiencies in stress response pathways in patient-derived cell lines. The aim of this study was to investigate whether these deficiencies manifested as increased susceptibility, as measured by cell viability, to a range of extrinsic stressors. We identified that patient-derived cells are more sensitive to mitochondrial complex I inhibition and hydrogen peroxide induced oxidative stress, than controls. Exposure to low levels (50 nM) of rotenone led to increased apoptosis in patient-derived cells. We identified an endogenous deficit in mitochondrial complex I in patient-derived cells, but this did not directly correlate with rotenone-sensitivity. We further characterized the sensitivity to rotenone and identified that it was partly associated with heat shock protein 27 levels. Finally, transcriptomic analysis following rotenone exposure revealed that patient-derived cells express a diminished response to rotenone-induced stress compared with cells from healthy controls. Our cellular model of idiopathic Parkinson's disease displays a clear susceptibility phenotype to mitochondrial stress. The determination of molecular mechanisms underpinning this susceptibility may lead to the identification of biomarkers for either disease onset or progression.

Deep brain stimulation for Parkinson disease in Australia: current scientific and clinical status.

There is currently no cure for Parkinson disease (PD). Disease management is directed primarily at motor symptom relief, but the impact of non-motor symptoms associated with PD should not be underestimated. Medical and surgical treatment options aim to increase functional independence and quality of life. Deep brain stimulation (DBS) has proven to be a safe, effective and cost-efficient surgical treatment option. In 2009, the Australian referral guidelines, developed to provide a synopsis of DBS therapy for PD, were introduced, and since then novel findings have been reported regarding the timing of intervention, target selection and symptom management. Our aim is to provide an update of DBS for PD in Australia. Intervention at earlier stages of the disease can potentially improve quality of life over a longer period with greater possibilities for meaningful social and professional contributions. For less responsive motor symptoms (e.g. freezing of gait, postural instability), the pedunculopontine nucleus has emerged as a promising new surgical target. Traditional PD treatment is focused on improvement of motor symptoms, but the disorder is also characterised by non-motor symptoms, often undiagnosed or undisclosed, that have the potential to impact quality of life to a greater extent than motor symptoms. It is essential to identify and routinely monitor for non-motor symptoms as they can emerge at all stages of the disease or can result from treatment. Many of these current advances require long-term monitoring of treatment outcomes to improve future clinical practice, refine patient selection and ensure best patient outcomes.

Nutritional status in Parkinson's disease patients undergoing deep brain stimulation surgery: a pilot study.

OBJECTIVES: People with Parkinson's disease (PD) are at higher risk of malnutrition due to PD symptoms and pharmacotherapy side effects. When pharmacotherapy is no longer effective for symptom control, deep-brain stimulation (DBS) surgery may be considered. The aim of this study was to assess the nutritional status of people with PD who may be at higher risk of malnutrition related to unsatisfactory symptom management with optimised medical therapy. DESIGN: This was an observational study using a convenience sample. SETTING: Participants were seen during their hospital admission for their deep brain stimulation surgery. PARTICIPANTS: People with PD scheduled for DBS surgery were recruited from a Brisbane neurological clinic (n=15). MEASUREMENTS: The Patient-Generated Subjective Global Assessment (PG-SGA), weight, height and body composition were assessed to determine nutritional status. RESULTS: Six participants (40%) were classified as moderately malnourished (SGA-B). Eight participants (53%) reported previous unintentional weight loss (average loss of 13%). On average, participants classified as well-nourished (SGA-A) were younger, had shorter disease durations, lower PG-SGA scores, higher body mass (BMI) and fat free mass indices (FFMI) when compared to malnourished participants (SGA-B). Five participants had previously received dietetic advice but only one in relation to unintentional weight loss. CONCLUSION: Malnutrition remains unrecognised and untreated in this group despite unintentional weight loss and presence of nutrition impact symptoms. Improving nutritional status prior to surgery may improve surgical outcomes.

Variability, regularity and coupling measures distinguish PD tremor from voluntary 5Hz tremor.

A characteristic of Parkinson's disease (PD) is the development of tremor within the 4-6Hz range. One method used to better understand pathological tremor is to compare the responses to tremor-type actions generated intentionally in healthy adults. This study was designed to investigate the similarities and differences between voluntarily generated 4-6Hz tremor and PD tremor in regards to their amplitude, frequency and coupling characteristics. Tremor responses for 8 PD individuals (on- and off-medication) and 12 healthy adults were assessed under postural and resting conditions. Results showed that the voluntary and PD tremor were essentially identical with regards to the amplitude and peak frequency. However, differences between the groups were found for the variability (SD of peak frequency, proportional power) and regularity (Approximate Entropy, ApEn) of the tremor signal. Additionally, coherence analysis revealed strong inter-limb coupling during voluntary conditions while no bilateral coupling was seen for the PD persons. Overall, healthy participants were able to produce a 5Hz tremulous motion indistinguishable to that of PD patients in terms of peak frequency and amplitude. However, differences in the structure of variability and level of inter-limb coupling were found for the tremor responses of the PD and healthy adults. These differences were preserved irrespective of the medication state of the PD persons. The results illustrate the importance of assessing the pattern of signal structure/variability to discriminate between different tremor forms, especially where no differences emerge in standard measures of mean amplitude as traditionally defined.

New evidence for, and challenges in, linking small CGG repeat expansion FMR1 alleles with Parkinson's disease.

We recently reported a significant increase in the frequency of carriers of grey zone (GZ) alleles of FMR1 gene in Australian males with Parkinson's disease (PD) from Victoria and Tasmania. Here, we report data comparing an independent sample of 817 PD patients from Queensland to 1078 consecutive Australian male newborns from Victoria. We confirmed the earlier finding by observing a significant excess of GZ alleles in PD (4.8%) compared to controls (1.5%). Although both studies provided evidence in support of an association between GZ-carrier status and increased risk for parkinsonism, the existing evidence in the literature from screening studies remains equivocal and we discuss the need for alternative approaches to resolve the issue.

Enhanced somatosensory information decreases postural sway in older people.

The somatosensory system plays an important role in balance control and age-related declines in somatosensory function have been implicated in falls incidence. Different types of insole devices have been developed to enhance somatosensory information and improve postural stability. However, they are often too complex and expensive to integrate into daily life and textured insole surfaces may provide an inexpensive and accessible means to enhance somatosensory input. This study investigated the effects of textured insole surfaces on postural sway in ten younger and seven older participants performing standing balance tests on a force plate under three insole surface conditions: (1) barefoot; (2) with hard; and (3), soft textured insole surfaces. With each insole surface, participants were tested under two vision conditions (eyes open, closed) on two standing surfaces (firm, foam). Four 30s trials were collected for different combinations of insole surface, standing surface and vision. Centre of pressure measurements included the range and standard deviation of anterior-posterior and medial-lateral displacement, path length and the 90% confidence elliptical area. Results revealed a significant Group*Surface*Insole interaction for five of the dependent variables. Compared to younger individuals, postural sway was greater in older people on both standing surfaces in the barefoot condition. However, both textured insole surfaces reduced postural sway for the older group especially in the eyes closed condition on a foam surface. These findings suggest that textured insole surfaces can reduce postural sway in older people, particularly during more challenging balance tasks. Textured insole surfaces may afford a low-cost means of decreasing postural sway, providing an important intervention in falls prevention.

Theoretical & experimental analysis of the Non Markov Parameter to detect low frequency synchronisation in time series analysis.

A theoretical investigation into the behaviour of the Non-Markov Parameter is performed from a signal processing perspective in contrast to previous methodologies based on stochastic processes theory. The results indicate that the NMP can be regarded as an informational metric which is indicative of the degree of low frequency synchronisation in a complex system. These results have deep implications for physiological analysis of biological systems where the presence of sychronisation is often a marker of pathological functioning. The NMP measure is then applied to in vivo micro-electrode recordings from the subthalamic nucleus.

Predictors of future falls in Parkinson disease.

BACKGROUND: Falls are a major health and injury problem for people with Parkinson disease (PD). Despite the severe consequences of falls, a major unresolved issue is the identification of factors that predict the risk of falls in individual patients with PD. The primary aim of this study was to prospectively determine an optimal combination of functional and disease-specific tests to predict falls in individuals with PD. METHODS: A total of 101 people with early-stage PD undertook a battery of neurologic and functional tests in their optimally medicated state. The tests included Tinetti, Berg, Timed Up and Go, Functional Reach, and the Physiological Profile Assessment of Falls Risk; the latter assessment includes physiologic tests of visual function, proprioception, strength, cutaneous sensitivity, reaction time, and postural sway. Falls were recorded prospectively over 6 months. RESULTS: Forty-eight percent of participants reported a fall and 24% more than 1 fall. In the multivariate model, a combination of the Unified Parkinson's Disease Rating Scale (UPDRS) total score, total freezing of gait score, occurrence of symptomatic postural orthostasis, Tinetti total score, and extent of postural sway in the anterior-posterior direction produced the best sensitivity (78%) and specificity (84%) for predicting falls. From the UPDRS items, only the rapid alternating task category was an independent predictor of falls. Reduced peripheral sensation and knee extension strength in fallers contributed to increased postural instability. CONCLUSIONS: Falls are a significant problem in optimally medicated early-stage PD. A combination of both disease-specific and balance- and mobility-related measures can accurately predict falls in individuals with PD.

Prevalence of smell loss in Parkinson's disease--a multicenter study.

Previous data on the prevalence of olfactory dysfunction in Parkinson's disease (PD) range from 45% to 90%. The present multicenter study aimed to provide data on the prevalence of smell loss in a large sample of PD patients from three independent populations. Olfactory sensitivity was tested in 400 patients from Australia, Germany, and The Netherlands by means of a psychophysical olfactory test, the "Sniffin' Sticks", which is comprised of 3 subtests of olfactory function. Out of the total number of patients 45.0% presented as functionally anosmic, 51.7% were hyposmic, whereas only 3.3% were normosmic. This indicates that 96.7% of PD patients present with significant olfactory loss when compared to young normosmic subjects. This figure falls to 74.5%, however, when adjusted to age-related norms. Thus, olfactory dysfunction should be considered as a reliable marker of the disease.

Utility of a patient survey in identifying fluctuations in early stage Parkinson's disease.

Motor and non-motor fluctuations are well known sequelae of dopaminergic therapies for Parkinson's disease (PD), particularly during the advanced stages. However, the prevalence of fluctuations early in the treatment course has been less well recognised and may be missed clinically if not specifically probed. We examined the used of a survey for this purpose. Patients to be surveyed were recruited by neurologists and geriatricians at 20 Australian centres. Patients had a diagnosis of idiopathic PD with a duration of fewer than 5 years and were considered by their treating physician to be non-fluctuating or had no change in their treatment plan in the prior 6 months. Patients, with or without assistance, completed a 19-item wearing-off questionnaire to assess the presence of motor and non-motor fluctuations that indicated early wearing-off. Investigators assessed the usefulness of the questionnaire in detecting fluctuations and guiding PD treatment. Of 105 patients recruited, 92 were eligible for analysis. There were 56 (61%) identified as having fluctuations. Patients with wearing-off were younger (mean 67 vs 72 years), and more likely to have had PD for more than 3 years. About half the patients (49%) were able to complete the questionnaire independently. Clinicians perceived the questionnaire as useful for detecting fluctuations and adjusting treatment. A simple and easily administered wearing-off questionnaire may be useful in the early detection of fluctuations in PD patients and assist in guiding therapy.

Differential time- and frequency-dependent structure of postural sway and finger tremor in Parkinson's disease.

The time- and frequency-dependent patterns of standing balance centre of pressure (COP) and finger postural/resting tremor of 12 older individuals and eight age-matched Parkinsonian (PD) participants (on/off medication) were investigated. Tremor and COP data were analysed using measures of signal amplitude (RMS), time-dependent structure (approximate entropy, ApEn), time-frequency analysis and synchrony (Cross ApEn). Results showed that the PD individuals had significantly greater tremor amplitude and COP excursions in comparison to controls. Differences in the time-dependent structure were also observed between groups. In comparison to the elderly, the resting/postural tremor output of the PD subjects was more regular (lower ApEn). However, for the postural measures, a reciprocal pattern was observed with the COP being more complex (higher ApEn). All group differences were magnified when the PD individuals were off their medication. There was also greater synchrony between tremor and postural sway for the PD individuals, indicating a high degree of association between these motor outputs. These results are consistent with the view that the neural signal driving the enhanced limb tremor in PD is propagated throughout the motor system, consequently emerging within the postural sway dynamics. This commonality of motor output may be a contributing factor in the differential pattern in the dynamics of effector signal structure in PD as a function of task.

Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial.

Olfactory ensheathing cells show promise in preclinical animal models as a cell transplantation therapy for repair of the injured spinal cord. This is a report of a clinical trial of autologous transplantation of olfactory ensheathing cells into the spinal cord in six patients with complete, thoracic paraplegia. We previously reported on the methods of surgery and transplantation and the safety aspects of the trial 1 year after transplantation. Here we address the overall design of the trial and the safety of the procedure, assessed during a period of 3 years following the transplantation surgery. All patients were assessed at entry into the trial and regularly during the period of the trial. Clinical assessments included medical, psychosocial, radiological and neurological, as well as specialized tests of neurological and functional deficits (standard American Spinal Injury Association and Functional Independence Measure assessments). Quantitative test included neurophysiological tests of sensory and motor function below the level of injury. The trial was a Phase I/IIa design whose main aim was to test the feasibility and safety of transplantation of autologous olfactory ensheathing cells into the injured spinal cord in human paraplegia. The design included a control group who did not receive surgery, otherwise closely matched to the transplant recipient group. This group acted as a control for the assessors, who were blind to the treatment status of the patients. The control group also provided the opportunity for preliminary assessment of the efficacy of the transplantation. There were no adverse findings 3 years after autologous transplantation of olfactory ensheathing cells into spinal cords injured at least 2 years prior to transplantation. The magnetic resonance images (MRIs) at 3 years showed no change from preoperative MRIs or intervening MRIs at 1 and 2 years, with no evidence of any tumour of introduced cells and no development of post-traumatic syringomyelia or other adverse radiological findings. There were no significant functional changes in any patients and no neuropathic pain. In one transplant recipient, there was an improvement over 3 segments in light touch and pin prick sensitivity bilaterally, anteriorly and posteriorly. We conclude that transplantation of autologous olfactory ensheathing cells into the injured spinal cord is feasible and is safe up to 3 years of post-implantation, however, this conclusion should be considered preliminary because of the small number of trial patients.

Stem cells and genetic disease.

Stem cell research is now a very broad field encompassing cells derived from all stages of life from the embryonic stem cells of the early blastocyst through to the adult stem cells of many tissues of the body. Adult stem cells from a variety of tissues are proving to be pluripotent and can differentiate into cell types different from the tissues from which they derive. Pre-clinical animal models indicate that adult stem cells do not cause tumours, not even, teratomas when transplanted. These properties, combined with the possibility of autologous transplantation, indicate significant advantages over embryonic stem cells in many proposed clinical applications.

Effects of subthalamic deep brain stimulation on noun/verb generation and selection from competing alternatives in Parkinson's disease.

BACKGROUND AND AIMS: Impaired generation of verbs relative to nouns has been reported in Parkinson's disease (PD) and has been associated with the frontal pathophysiology of PD. The aim of the present study was to measure noun/verb generation abilities in PD and to determine whether noun/verb generation is affected by stimulation of the subthalamic nucleus (STN). PATIENTS AND METHODS: 8 participants who had been diagnosed with PD and had received surgery for deep brain stimulation (DBS) of the STN as well as 15 control participants completed a noun/verb generation task with four probe-response conditions-namely, noun-noun, verb-noun, noun-verb and verb-verb conditions. Patients with PD were assessed while receiving STN stimulation and without stimulation. RESULTS: During the off stimulation condition, patients with PD presented with a selective deficit in verb generation compared with control participants. However, when receiving STN stimulation, patients with PD produced significantly more errors than controls during the noun-noun and verb-verb conditions, supporting evidence from previous studies that STN stimulation modulates a frontotemporal network associated with word generation. Finally, errors during verb generation were significantly correlated with item selection constraint (ie, the degree to which a response competes with other response alternatives) in the on stimulation condition, but not the off stimulation condition. CONCLUSION: Our results suggest that STN stimulation affects the ability to select from many competing lexical alternatives during verb generation.

Bilateral tremor relations in Parkinson's disease: effects of mechanical coupling and medication.

The aim of the present study was to examine the dynamics of bilateral multiple segment resting and postural tremor in 12 young, older subjects and eight Parkinson's (PD) patients in their different medication states. A second aim was to investigate whether bilateral independence of upper limb tremor was preserved for PD patients with amplified tremor under conditions where no upper limb segment was supported. Under these conditions, the likelihood for mechanical transmission between segments was increased. Tremor was recorded, bilaterally, from the hand and finger segments of all subjects. In addition to the PD subjects exhibiting greater tremor under both on/off medication states than the young/old control subjects, the tremor increase within limb from the hand to the finger was 2-3 times greater for the PD group in comparison to the healthy subjects. Despite this increased tremor, no differences were observed in the level of coupling between limbs across groups. Furthermore, the degree of coupling between limbs for the PD group was unaffected by their medication state. Overall, these results demonstrate that bilateral independence of tremor in PD participants is preserved despite conditions which maximised the chance of increased coupling.

Rapid subthalamic nucleus deep brain stimulation lead placement utilising CT/MRI fusion, microelectrode recording and test stimulation.

Subthalamic nucleus (STN) deep brain stimulation (DBS) has become an established treatment strategy for patients with medically refractory Parkinson's disease (PD). There are however numerous strategies employed for STN lead placement. Variations include method of STN localisation, use of microelectrode recording, number of microelectrode recording passes and time taken for the procedure. We describe a relatively simple and rapid technique of STN lead placement utilising CT/ MRI image fusion, microelectrode recording and test stimulation. The first 58 consecutive patients undergoing STN DBS were assessed pre- and post-operatively. UPDRS scores, medication use and any surgical complication were assessed. Bilateral STN DBS was an efficacious treatment option for medically refractory PD. We have described a technique which can be performed with effect and low morbidity, and in a time which is well tolerated by patients.

Quantitative assessment of driving performance in Parkinson's disease.

OBJECTIVES: The primary aim of this study was to determine how Parkinson's disease (PD) affects driving performance. It also examined whether changes in driver safety were related to specific clinical disease markers or an individual's self rating of driving ability. METHODS: The driving performance of 25 patients with idiopathic PD and 21 age matched controls was assessed on a standardised open road route by an occupational therapist and driving instructor, to provide overall safety ratings and specific driving error scores. RESULTS: The drivers with PD were rated as significantly less safe (p<0.05) than controls, and more than half of the drivers with PD would not have passed a state based driving test. The driver safety ratings were more strongly related to disease duration (r = -0.60) than to their on time Unified Parkinson's Disease Rating Scale (r = -0.24). Drivers with PD made significantly more errors than the control group during manoeuvres that involved changing lanes and lane keeping, monitoring their blind spot, reversing, car parking, and traffic light controlled intersections. The driving instructor also had to intervene to avoid an incident significantly more often for drivers with PD than for controls. Interestingly, driver safety ratings were unrelated to an individual's rating of their own driving performance, and this was the case for all participants. CONCLUSIONS: As a group, drivers with PD are less safe to drive than age matched controls. Standard clinical markers cannot reliably predict driver safety. Further studies are required to ascertain whether the identified driving difficulties can be ameliorated.

A novel screen for nuclear mitochondrial gene associations with Parkinson's disease.

Genetic factors play an important role in the aetiology of Parkinson's disease (PD). We have screened nuclear genes encoding subunits of mitochondrial complex I for associations between single nucleotide polymorphisms (SNPs) and PD. Abnormal functioning of complex I is well documented in human PD. Moreover, toxicological inhibition of complex I can lead to parkinsonism in animals. Thus, commonly occurring variants in these genes could potentially influence complex I function and the risk of developing PD. A sub-set of 70 potential SNPs in 31 nuclear complex I genes were selected and association analysis was performed on 306 PD patients plus 321 unaffected control subjects. Genotyping was performed using the DASH method. There was no evidence that the examined SNPs were significant genetic risk factors for PD, although this initial screen could not exclude the possibility that other disease-influencing variations exist within these genes.

Defining a role for the subthalamic nucleus within operative theoretical models of subcortical participation in language.

OBJECTIVE: To investigate the effects of bilateral, surgically induced functional inhibition of the subthalamic nucleus (STN) on general language, high level linguistic abilities, and semantic processing skills in a group of patients with Parkinson's disease. METHODS: Comprehensive linguistic profiles were obtained up to one month before and three months after bilateral implantation of electrodes in the STN during active deep brain stimulation (DBS) in five subjects with Parkinson's disease (mean age, 63.2 years). Equivalent linguistic profiles were generated over a three month period for a non-surgical control cohort of 16 subjects with Parkinson's disease (NSPD) (mean age, 64.4 years). Education and disease duration were similar in the two groups. Initial assessment and three month follow up performance profiles were compared within subjects by paired t tests. Reliability change indices (RCI), representing clinically significant alterations in performance over time, were calculated for each of the assessment scores achieved by the five STN-DBS cases and the 16 NSPD controls, relative to performance variability within a group of 16 non-neurologically impaired adults (mean age, 61.9 years). Proportions of reliable change were then compared between the STN-DBS and NSPD groups. RESULTS: Paired comparisons within the STN-DBS group showed prolonged postoperative semantic processing reaction times for a range of word types coded for meanings and meaning relatedness. Case by case analyses of reliable change across language assessments and groups revealed differences in proportions of change over time within the STN-DBS and NSPD groups in the domains of high level linguistics and semantic processing. Specifically, when compared with the NSPD group, the STN-DBS group showed a proportionally significant (p<0.05) reliable improvement in postoperative scores achieved on the word test-revised (TWT-R), as well as a reliable decline (p<0.01) in the accuracy of lexical decisions about words with many meanings and a high degree of relatedness between meanings. CONCLUSIONS: Bilateral STN-DBS affects certain aspects of linguistic functioning, supporting a potential role for the STN in the mediation of language processes.