The Use of Data from the Parkinson's KinetiGraph to Identify Potential Candidates for Device Assisted Therapies.

Device-assisted therapies (DAT) benefit people with Parkinsons Disease (PwP) but many referrals for DAT are unsuitable or too late, and a screening tool to aid in identifying candidates would be helpful. This study aimed to produce such a screening tool by building a classifier that models specialist identification of suitable DAT candidates. To our knowledge, this is the first objective decision tool for managing DAT referral. Subjects were randomly assigned to either a construction set (n = 112, to train, develop, cross validate, and then evaluate the classifier's performance) or to a test set (n = 60 to test the fully specified classifier), resulting in a sensitivity and specificity of 89% and 86.6%, respectively. The classifier's performance was then assessed in PwP who underwent deep brain stimulation (n = 31), were managed in a non-specialist clinic (n = 81) or in PwP in the first five years from diagnosis (n = 22). The classifier identified 87%, 92%, and 100% of the candidates referred for DAT in each of the above clinical settings, respectively. Furthermore, the classifier score changed appropriately when therapeutic intervention resolved troublesome fluctuations or dyskinesia that would otherwise have required DAT. This study suggests that information from objective measurement could improve timely referral for DAT.

Measurement of Axial Rigidity and Postural Instability Using Wearable Sensors.

Axial Bradykinesia is an important feature of advanced Parkinson's disease (PD). The purpose of this study is to quantify axial bradykinesia using wearable sensors with the long-term aim of quantifying these movements, while the subject performs routine domestic activities. We measured back movements during common daily activities such as pouring, pointing, walking straight and walking around a chair with a test system engaging a minimal number of Inertial Measurement (IM) based wearable sensors. Participants included controls and PD patients whose rotation and flexion of the back was captured by the time delay between motion signals from sensors attached to the upper and lower back. PD subjects could be distinguished from controls using only two sensors. These findings suggest that a small number of sensors and similar analyses could distinguish between variations in bradykinesia in subjects with measurements performed outside of the laboratory. The subjects could engage in routine activities leading to progressive assessments of therapeutic outcomes.

Can Valproic Acid Regulate Neurogenesis from Nestin+ Cells in the Adult Midbrain?

Degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) causes the motor symptoms (e.g. tremor, muscle rigidity, bradykinesia, postural instability) of Parkinson's disease (PD). It is generally agreed that replacing these neurons will provide better motor symptom relief and fewer side effects than current pharmacotherapies. One potential approach to this is up-regulating endogenous DA neurogenesis in SNc. In the present study, we conducted bioinformatics analyses to identify signalling pathways that control expression of Pax6 and Msx1 genes, which have been identified as potentially important neurogenic regulators in the adult midbrain. From this Valproic acid (VPA) was identified as a regulator of these pathways, and we tested VPA for its ability to regulate midbrain neurogenesis in adult mice. VPA was infused directly into the midbrain of adult NesCreERT2/R26eYFP mice using osmotic pumps attached to implanted cannula. These mice enable permanent eYFP+ labelling of adult Nestin-expressing neural precursor cells and their progeny/ontogeny. VPA did not affect the number of eYFP+ midbrain cells, but significantly reduced the number of Pax6+, Pax6+/NeuN+, eYFP+/NeuN+ and eYFP-/NeuN+ cells. However, this reduction in NeuN expression was probably via VPA's Histone de-acetylase inhibitory properties rather than reduced neuronal differentiation by eYFP + cells. We conclude that Pax6 and Msx1 are not viable targets for regulating neurogenesis in the adult midbrain.

Towards a Better Treatment Option for Parkinson's Disease: A Review of Adult Neurogenesis.

The motor symptoms of Parkinson's disease (PD) are caused by degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) of midbrain. Given the fact that current treatment options are mostly symptomatic and based on increasing DA level in the nigrostriatal system, it is generally believed the most effective and long-lasting treatment for PD motor symptoms will be replacing SNc DA cells, either by endogenous repair (i.e. neurogenesis) or cell transplantation. While cell transplantation is hindered by failure of acquisition and maintenance of the DA phenotype by transplanted cells, hope rests upon non-invasive cell replacement therapy (CRT) with endogenous neural stem cells, which have the potential to give rise to new neurons including DA neurons. Understanding underlying mechanisms and signalling pathways of neurogenesis in the adult brain could shed light on obstacles to achieve effective CRTs and better treatments for PD. This paper first reviews different therapeutic strategies in context of PD along with their advantages and disadvantages followed by an extensive review of adult neurogenesis.

Sensor Measurements Can Characterize Fluctuations and Wearing Off in Parkinson's Disease and Guide Therapy to Improve Motor, Non-motor and Quality of Life Scores.

Objectives: The aim was to examine the role of sensor measurement in identifying and managing fluctuations in bradykinesia of Parkinson's Disease. Method: Clinical scales and data from wearable sensors obtained before and after optimization of treatment from 107 participants who participated in a previous study was used. Fluctuators were identified by a levodopa response or wearing off in their sensor data and were subdivided according to whether the sensor's bradykinesia scores were in target range, representing acceptable bradykinesia for part of the dose (Controlled Fluctuator: n = 22) or above target for the whole dose period (Uncontrolled Fluctuator; n = 28). Uncontrolled Non-fluctuators (n = 24) were cases without a levodopa response or wearing-off and sensor bradykinesia scores above target throughout the day (un-controlled). Controlled Non-fluctuators (n = 33) were below target throughout the day (controlled) and used as a reference for good control (MDS-UPDRS III = 33 ± 8.6 and PDQ39 = 28 ± 18). Results: Treating Fluctuators significantly improved motor and quality of life scores. Converting fluctuators into Controlled Non-fluctuators significantly improved motor, non-motor and quality of life scores and a similar but less significant improvement was obtained by conversion to a Controlled Fluctuator. There was a significantly greater likelihood of achieving these changes when objective measurement was used to guide management. Conclusions: The sensor's classification of fluctuators bore a relation to severity of clinical scores and treatment of fluctuation improved clinical scores. The sensor measurement aided in recognizing and removing fluctuations with treatment and resulted in better clinical scores, presumably by assisting therapeutic decisions.

Assessment of Wearing Off in Parkinson's disease using objective measurement.

BACKGROUND: Development of "Wearing Off" (WO) of motor and non-motor function in Parkinson's disease (PD) adversely affects quality of life. This suggest that identifying and treating WO is important. However, identification of WO depends on people with PD (PwP) recognising and reporting WO and there is a perception that WO may be significantly underestimated. OBJECTIVE: We investigate the feasibility of identifying "Wearing Off" using objective measurement and assess the clinical benefit in rectifying it. METHOD: In this study, 200 PwP were studied for evidence of WO using a continuously worn wearable system. Eighty-five patients (43%) were found to have WO and treatment was changed to mitigate the effects of WO. RESULTS: Factors, such as duration of disease, high baseline MDS-UPDRS (motor component), high Percent Time in Bradykinesia (PTB), high Levodopa Equivalent Daily Dose (LEDD), frequent Levodopa doses and younger age of onset, are associated with severity of motor complications. Patients with more severe WO experienced worse motor and non-motor symptoms and lower quality of life. Quality of life significantly improved in PwP when WO was treated. CONCLUSION: The findings reported in this study provide evidence that identifying and treating WO improves outcomes of PwP and that objective measurements may help clinicians to identify and treat WO.

Interventions to support Choosing Wisely for coagulation studies in the emergency department.

OBJECTIVE: To evaluate the effectiveness of two different strategies designed to facilitate implementation of Choosing Wisely Australia guidelines, aiming to reduce unnecessary coagulation study blood tests in patients presenting to a metropolitan hospital ED. METHOD: In this real-world quality improvement study, the first intervention tested was an education strategy. The second intervention was physically removing coagulation pathology tubes from the bedside trolleys in the ED. Data were collected about clinical appropriateness of testing, as per the Choosing Wisely Australia guideline and total volume of coagulation studies ordered. RESULTS: No reduction in inappropriate coagulation testing was observed following the education intervention whereas a significant reduction in inappropriate coagulation testing was seen after the second intervention (inappropriate testing reduced from 73.8% to 53.0%). CONCLUSION: Physically removing coagulation pathology tubes from the trolleys was found to be effective at reducing unnecessary testing.

Comparative review of adult midbrain and striatum neurogenesis with classical neurogenesis.

Parkinson's Disease (PD) motor symptoms are caused by loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) of the midbrain. Dopamine cell replacement therapy (DA CRT), either by cell transplantation or endogenous repair, has been a potential treatment to replace dead cells and improve PD motor symptoms. Adult midbrain and striatum have been studied for many years to find evidence of neurogenesis. Although the literature is controversial, recent research has revived the possibility of neurogenesis here. This paper aims to review the process of neurogenesis (by focusing on gene expression patterns) in the adult midbrain/striatum and compare it with classical neurogenesis that occurs in developing midbrain, Sub Ventricular Zone (SVZ) and Sub Granular Zone (SGZ) of the adult brain.

Effect of Parkinsonism on Proximal Unstructured Movement Captured by Inertial Sensors.

In this study, we endeavour to measure characteristic movements of patients with Parkinson's disease (PD). Our eventual aim is to obtain the severity of these exhibited movements entirely based on measurements conducted in un-clinical environments. Indeed, we investigate the feasibility of capturing such un-structured movements using wearable sensors. In particular, as Bradykinesia and axial Bradykinesia are vital characteristics yet challenging to measure, we design a test system of Inertial Measurement (IM) based wearable sensors in order to capture the affected movements of the back. The study evaluated the characteristics of PD patients during the unstructured activities. Our analysis captured back flexibility based on frequency information of the sensors attached to the human back. Satisfactory classification in each test confirms that this testing system can identify as well as evaluate PD patients using a minimal number of sensors during these unstructured movements. Our objective is to enhance the uptake and promote the use of wearable sensors in longer term monitoring scenarios relevant to non-clinical environments. Thus, we envisage clinicians monitoring the progress due to the treatment of patients residing in their homes assisted by sensors with enhanced wearability.

Objective measurement in routine care of people with Parkinson's disease improves outcomes.

It is common in medicine to titrate therapy according to target ranges of objectively measured parameters. Objective measurement of motor function is available for Parkinson's Disease (PD), making it possible to optimise therapy and clinical outcomes. In this study, an accelerometry based measurement and predefined target ranges were used to assess motor function in a Northern Tasmania PD cohort managed by a Movement Disorder clinic. Approximately 40% (n = 103) of the total PD population participated in this study and motor scores were within target in 22%. In the 78% above target, changes in oral therapy were recommended in 74%, Advanced Therapy in 12% and treatment was contraindicated in 9%. Following changes in oral therapy, there was a further objective measurement and clinical consultation to establish whether scores had reached target range: if so subjects left the study, otherwise further changes of therapy were recommended (unless contraindications were present). Seventy-seven cases completed the study, with 48% achieving target (including 22% at outset), Advanced Therapy recommended in 19% and contraindications preventing any change in therapy in 17%. In the 43% of cases in whom oral therapy was changed, total UPDRS improved significantly (effect size = 8) as did the PDQ39 in cases reaching target. NMS Quest and MOCA scores also improved significantly. This study shows that many people in a representative cohort of PD would benefit from objective assessment and treatment of their PD features against a target.

The use of accelerometry as a tool to measure disturbed nocturnal sleep in Parkinson's disease.

Sleep disturbances are common in Parkinson's disease (PD). We used the Parkinson's KinetiGraph (PKG), an objective movement recording system for PD to assess night time sleep in 155 people aged over 60 and without PD (controls), 72 people with PD (PwP) and 46 subjects undergoing a Polysomnogram (PSG: 36 with sleep disorder and 10 with normal sleep). The PKG system uses a wrist worn logger to capture acceleration and derive a bradykinesia score (BKS) every 2 min over 6 days. The BKS ranges from 0-160 with higher scores associated with lesser mobility. Previously we showed that BKS > 80 were associated with day time sleep and used this to produce scores for night time sleep: Efficiency (Percent time with BKS > 80), Fragmentation (Average duration of runs of BKS > 80) and Sleep Quality (BKS > 111 as a representation of atonia). There was a fair association with BKS score and sleep level as judged by PSG. Using these PKG scores, it was possible to distinguish between normal and abnormal PSG studies with good Selectivity (86%) and Sensitivity (80%). The PKG's sleep scores were significantly different in PD and Controls and correlated with a subject's self-assessment (PDSS 2) of the quality, wakefulness and restlessness. Using both the PDSS 2 and the PKG, it was apparent that sleep disturbances were apparent early in disease in many PD subjects and that subjects with poor night time sleep were more likely to have day time sleepiness. This system shows promise as a quantitative score for assessing sleep in Parkinson's disease.

Evaluation of the Parkinson's KinetiGraph in monitoring and managing Parkinson's disease.

INTRODUCTION: While objective measurement is routine in clinical care of most conditions, this has not been the case for Parkinson's Disease. Recent innovations make objective measurement in Parkinson's Disease possible and its utility and how this should be assessed is discussed here. Areas covered: Whilst therapies are effective in Parkinson's Disease, symptoms fluctuate in relation to treatment over the course of the day. Objective measurement makes it possible to assess symptom control, whether treatment is required and whether it achieved control. Objective measurement makes it possible to consider targets for therapeutic control and to begin an assessment of the value of improved control. Evidence for the effect of improved measurement on outcomes is only beginning to emerge. As symptom severity relates to quality of life and costs, reducing clinical scores and fluctuations through objective measurement is in the interest of both the patient and the health system. Expert commentary: In broad terms objective measurement should be used to identify patients whose symptoms lie outside the target range and then to assess whether therapy was effective in bringing them into control. While this is relevant to all stages of Parkinson's Disease specific clinical situations where this had greatest impact are discussed.

An investigation of gene expression in single cells derived from Nestin-expressing cells in the adult mouse midbrain in vivo.

Generation of new dopamine (DA) neurons in the adult midbrain is a controversial issue in development of better treatments for Parkinson's disease (PD). Previous research suggests Nestin-expressing neural precursor cells (NPCs) have a propensity to differentiate into neurons here, including DA neurons. In the present study we sought confirmation of this by studying gene expression in single Nestin-expressing cells and their progeny/ontogeny within the adult mouse midbrain. Cells were identified by administering a pulse of Tamoxifen to adult Nestin-CreERT2×R26eYFP transgenic mice. Samples of cytoplasm were harvested 4 days to 8 months later from individual eYFP+ cells in acutely prepared midbrain slices and analysed by RT-qPCR for gene expression. Remarkably, most eYFP+ cells co-expressed genes associated with mature (including DA) neurons (i.e. NeuN, Gad1, Gad2, vGlut2, TH and/or D2R) and neurogenesis (i.e. Ki67, Dcx, Ncam, Pax6, Ngn2 and/or Msx1), and this was true at all time-points following Tamoxifen. Indeed, cell proliferation genes (Nestin, Ki67) were exclusively expressed by eYFP+ cells with mature neuronal morphology and gene expression, and only at early time-points after Tamoxifen. Expression of proneuronal genes (Pax6, Msx1, Ngn2) was, however, higher in eYFP+ cells with immature morphology compared with mature morphology. Gene expression bore no relationship to cell location indicating that, in contrast to development, Nestin-expressing cells arise throughout the midbrain parenchyma and do not migrate long distances. On the other hand, gene expression did change with time after Tamoxifen, although not in a way consistent with neurogenesis. Overall, our results suggest that Nestin expression in the adult midbrain occurs in mature neurons, casting doubt on the premise of neurogenesis from Nestin+ NPCs here.

Electrophysiological and gene expression characterization of the ontogeny of nestin-expressing cells in the adult mouse midbrain.

The birth of new neurons, or neurogenesis, in the adult midbrain is important for progressing dopamine cell-replacement therapies for Parkinson's disease. Most studies suggest newborn cells remain undifferentiated or differentiate into glia within the adult midbrain. However, some studies suggest nestin+neural precursor cells (NPCs) have a propensity to generate new neurons here. We sought to confirm this by administering tamoxifen to adult NesCreERT2/R26eYFP transgenic mice, which permanently labelled adult nestin-expressing cells and their progeny with enhanced yellow fluorescent protein (eYFP). eYFP+ midbrain cells were then characterized 1-32weeks later in acutely prepared brain slices using whole-cell patch clamp electrophysiology combined with single-cell RT-qPCR. Most eYFP+ cells exhibited a mature neuronal phenotype with large amplitude fast action potentials (APs), spontaneous post-synaptic currents (sPSCs), and expression of 'mature' neuronal genes (NeuN, Gad1, Gad2 and/or VGLUT2). This was the case even at the earliest time-point following tamoxifen (i.e. 1week). In comparison to neighboring eYFP- (control) cells, eYFP+ cells discharged more APs per unit current injection, and had faster AP time-to-peak, hyperpolarized resting membrane potential, smaller membrane capacitance and shorter duration sPSCs. eYFP+ cells were also differentiated from eYFP- cells by increased expression of 'immature' pro-neuronal genes (Pax6, Ngn2 and/or Msx1). However, further analyses failed to reveal evidence of a place of birth, neuronal differentiation, maturation and integration indicative of classical neurogenesis. Thus our findings do not support the notion that nestin+NPCs in the adult SNc and midbrain generate new neurons via classical neurogenesis. Rather, they raise the possibility that mature neurons express nestin under unknown circumstances, and that this is associated with altered physiology and gene expression.

Evidence of functional duplicity of Nestin expression in the adult mouse midbrain.

Whether or not neurogenesis occurs in the adult substantia nigra pars compacta (SNc) is an important question relevant for developing better treatments for the motor symptoms of Parkinson's disease (PD). Although controversial, it is generally believed that dividing cells here remain undifferentiated or differentiate into glia, not neurons. However, there is a suggestion that Nestin-expressing neural precursor cells (NPCs) in the adult SNc have a propensity to differentiate into neurons, which we sought to confirm in the present study. Adult (>8-weeks old) transgenic NesCreERT2/GtROSA or NesCreERT2/R26eYFP mice were used to permanently label Nestin-expressing cells and their progeny with ß-galactosidase (ß-gal) or enhanced yellow fluorescent protein (eYFP), respectively. Most ß-gal+ or eYFP+ cells were found in the ependymal lining of the midbrain aqueduct (Aq) and in the midline ventral to Aq. Smaller but significant numbers were in the periaqueductal gray (PAG), the ventral tegmental area (VTA), and in SNc. Low-level basal proliferation was evidenced by a modest increase in number of ß-gal+ or eYFP+ cells over time, fewer ß-gal+ or eYFP+ cells when mice were administered the anti-mitotic agent Cytarabine, and incorporation of the proliferation marker bromodeoxyuridine (BrdU) in a very small number of ß-gal+ cells. No evidence of migration was found, including no immunoreactivity against the migration markers doublecortin (DCX) or polysialic acid neural cell adhesion molecule (PSA-NCAM), and no dispersal of ß-gal+ or eYFP+ cells through the midbrain parenchyma over time. However, ß-gal+ or eYFP+ cells did increase in size and express higher levels of mature neuronal genes over time, indicating growth and neuronal differentiation. In mice whose SNc dopamine neurons had been depleted with 6-hydroxy-dopamine, a model of PD, there were ~2-fold more ß-gal+ cells in SNc specifically, although the proportion that were also NeuN+ was not affected. Remarkably, as early as 4days following putative Nestin-expression, many ß-gal+ or eYFP+ cells had mature neuronal morphology and were NeuN+. Furthermore, mature neuronal ß-gal+ cells were immunoreactive against the self-renewal or pluripotency marker sex determining region Y-box 2 (Sox2). Overall, our data support the notion that some Nestin-expressing, presumably NPCs, have a limited capacity for proliferation, no capacity for migration, and a propensity to generate new neurons within the microenvironment of the adult midbrain. However, our data also suggest that significant numbers of extant midbrain neurons express Nestin and other classical neurogenesis markers in contexts that are presumably not neurogenic. These findings foreshadow duplicitous roles for Nestin and other molecules that are traditionally associated with neurogenesis in the adult midbrain, which should be considered in future PD research.

An Ambulatory Tremor Score for Parkinson's Disease.

BACKGROUND: While tremor in Parkinson's Disease (PD) can be characterised in the consulting room, its relationship to treatment and fluctuations can be clinically helpful. OBJECTIVE: To develop an ambulatory assessment of tremor of PD. METHODS: Accelerometry data was collected using the Parkinson's KinetiGraph System (PKG, Global Kinetics). An algorithm was developed, which could successfully distinguish been subjects with a resting or postural tremor that involved the wrist whose frequency was greater than 3 Hz. Percent of time that tremor was present (PTT) between 09 : 00 and 18 : 00 was calculated. RESULTS: This algorithm was applied to 85 people with PD who had been assessed clinically for the presence and nature of tremor. The Sensitivity and Selectivity of a PTT ≥0.8% was 92.5% and 92.9% in identifying tremor, providing that the tremor was not a fine kinetic and postural tremor or was not in the upper limb. A PTT >1% provide high likely hood of the presence of clinical meaningful tremor. These cut-offs were retested on a second cohort (n = 87) with a similar outcome. The Sensitivity and Selectivity of the combined group was 88.7% and 89.5% respectively. Using the PTT, 50% of 22 newly diagnosed patients had a PTT >1.0%.The PKG's simultaneous bradykinesia scores was used to find a threshold for the emergence of tremor. Tremor produced artefactual increase in the PKG's dyskinesia score in 1% of this sample. CONCLUSIONS: We propose this as a means of assessing the presence of tremor and its relationship to bradykinesia.