Meghan Thomas

Exercise and Parkinson's: benefits for cognition and quality of life

Cruise KE, Bucks RS, Loftus AM, Newton RU, Pegoraro R, Thomas MG. Exercise and Parkinson’s: benefits for cognition and quality of life.
Acta Neurol Scand: 2011: 123: 13–19.
© 2010 The Authors Journal compilation

Coping processes and health‐related quality of life in Parkinson's disease

This study investigated the predictive value of various coping processes for the psychological and disease specific aspects of health‐related quality of life (HRQoL) in Parkinsons disease (PD).

Perplexing Pax: From Puzzle to Paradigm

Pax transcription factors are critical for the development of the central nervous system (CNS) where they have a biphasic role, initially dictating CNS regionalization, while later orchestrating differentiation of specific cell subtypes. While a plethora of expression, misexpression, and mutation studies lend support for this argument and clarify the importance of Pax genes in CNS development, less well understood, and more perplexing, is the continued Pax expression in the adult CNS. In this article we explore the mechanism of action of Pax genes in general, and while being cognizant of existing developmental data, we also draw evidence from (1) adult progenitor cells involved in regeneration and tissue maintenance, (2) specific expression patterns in fully differentiated adult cells, and (3) analysis of direct target genes functioning downstream of Pax proteins. From this, we present a more encompassing theory that Pax genes are key regulators of a cells measured response to a dynamic environment. Developmental Dynamics 237:2791–2803, 2008.

Bone marrow stromal cells as replacement cells for Parkinson’s disease: generation of an anatomical but not functional neuronal phenotype

The focus of cell replacement therapies (CRTs) for Parkinsons disease has been on delivering dopamine-producing cells to the striatum. Fetal grafts have proven the feasibility of this approach, but an appropriate source of replacement cells has restricted the clinical translation. Bone marrow stromal cells (BMSCs) have been heralded as an ideal source of dopaminergic (DAergic) replacement cells, as they are viewed as ethically acceptable, easily procured, and readily expanded. It is known that they confer functional benefits, particularly in stroke models, through the release of neurotrophic factors, but their transdifferentiation into neurons is still under contention. We sought to evaluate the neuronal phenotype and functional capacity of adult rat BMSCs after exposure to a novel multistep in vitro differentiation protocol compared with cells exposed to other reported neuronal differentiation conditions. We employed a systematic, comprehensive method of assessment to determine the neuronal differentiation capacity of BMSCs. Our fluorescence-activated cell sorting, immunofluorescent and semiquantitative polymerase chain reaction results confirmed that undifferentiated BMSCs isolated based on their adherence to plastic are of mesenchymal origin and express a range of lineage markers. After exposure to preinduction and neuronal induction steps, BMSCs down-regulate markers of other lineages but fail, as assessed by patch clamp, to differentiate into functional neurons. Thus, for BMSCs to be considered a source of DAergic neuronal replacement cells, their ability to transdifferentiate terminally along a neuronal lineage first must be clarified before attempting to direct more complex specification process required for them to be used in Parkinsons-disease-focused CRTs.

Personality affects aspects of health-related quality of life in Parkinson's disease via psychological coping strategies

BACKGROUND Personality traits influence health-related quality of life (HRQoL) in Parkinsons disease (PD). Further, an individuals 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 (Parkinsons 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.

Neurosurgical convection-enhanced delivery of treatments for Parkinson’s disease

Convection-enhanced delivery (CED) is a promising neurosurgical technique for the delivery of potential therapeutic agents to the Parkinsons disease (PD)-affected striatum. CED utilises stereotactic insertion of a catheter to the striatum and continuous infusion to distribute agents in the brain parenchyma. Insufficient attention to the details of CED may have contributed to early failures of translating candidate therapeutic agents from the laboratory to PD patients. A literature review was performed to examine the factors that govern CED in the laboratory as well as translation in PD and we found that although there have been significant developments in implant design, infusion parameters and infusate composition, there have not been enough comparative trials of different technologies. Further optimisation of CED is required before it can be applied in the clinical setting and this will require a step-by-step breakdown of the different elements of delivery for independent testing. We conclude that CED is a promising technique for delivering therapeutic agents to the striatum for the treatment of PD but further refinements are necessary for successful clinical translation. The risk is that early clinical translation of exciting new therapies may lead to therapeutic failure which is not due to the agent in question but simply the neurosurgical delivery.

Expression profiles suggest a role for Pax7 in the establishment of tectal polarity and map refinement

The role for Pax7 in establishing tectal polarity and map refinement was authenticated by gene expression studies in vivo and in vitro. Throughout development (stages E2–E12 were examined) a rostrallow-caudalhigh and dorsalhigh-ventrallow Pax7 expression gradient was detected immunohistochemically in the chick optic tectum, indicating a role for Pax7 in establishing tectal polarity. Chick retino-recipient tectal cells positive for Pax7 also co-expressed ephrin-A2, a molecule involved in the establishment and refinement of the retinotopic map. In vitro, PAX7 up-regulated ephrin-A2 when transfected into undifferentiated P19 cells; cells became negative for both Pax7 and ephrin-A2 protein following treatment with anti-sense oligonucleotides. These results suggest that in addition to being involved in the early establishment of tectal polarity, Pax7 plays a later role in retino-tectal map formation and refinement.

Moving Beyond Tyrosine Hydroxylase to Define Dopaminergic Neurons for Use in Cell Replacement Therapies for Parkinson's Disease

Cell replacement therapies are an attractive mode of treatment for neurodegenerative disorders as they have the potential to alleviate or modify disease symptoms and restore function. In Parkinsons disease, the cell type requiring replacement is dopamine-producing neurons of the midbrain. The source of replacement cells is contentious, with opinion still evolving. Clinical trials have previously used fetal brain tissue; however, this will likely be superseded by the use of embryonic or induced pluripotent stem cells, due to their greater availability and homogeneity. One significant caveat in the use of any cell source for therapy is that cells must first be adequately characterised and purified. The gold standard marker in the identification of dopaminergic neurons is tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis, catalyzing the conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine. However, there are multiple ways of measuring TH readout, and potential flaws in the fidelity of TH expression. This review will look at the complex regulatory mechanisms that govern different facets of TH expression, including reported differences in TH expression in vitro and in vivo. We will also examine the regulation of the TH gene; assessing the which, the where and the when of TH expression. We will look at how knowledge of regulation of the TH gene can be utilised to enhance research efforts. And, finally we will delve into the transcription factors that govern elements of TH expression, and which may prove more effective for defining appropriate dopaminergic neuron precursor cells.

A multiphasic role for Pax7 in tectal development

The optic tectum differentiates from the mesencephalic alar plate and matures into a characteristically laminated structure. Evidence presented here suggests a role for Pax7 in all stages of development of tectal architecture, from regionalisation to specification of neurons and tectal topography. Analysis of Pax7 expression profiles over a range of developmental stages (E2–E12) suggests a biphasic role for Pax7: initially Pax7 expressing cells in the proliferative neuroepithelial layer establish tectal polarity whereas later Pax7 is expressed in neurons of the retino-recipient precursor stratum griseum et fibrosum superficiale (sgfs) laminae where graded levels may establish tectal topography. Furthermore, co-localisation immunofluorescence confirmed that Pax7 is initially expressed in the majority of proliferative neuroepithelial cells and later in a subset of neurons of the sgfs laminae.

The relationship between sleep and cognition in Parkinson's disease: A meta-analysis

It is well established that sleep disorders have neuropsychological consequences in otherwise healthy people. Studies of night-time sleep problems and cognition in Parkinsons disease (PD), however, paint a mixed picture, with many reporting no relationship between sleep problems and neuropsychological performance. This review aimed to meta-analyse this research and to examine the factors underlying these mixed results. A literature search was conducted of published and unpublished studies, resulting in 16 papers that met inclusion criteria. Data were analysed in the domains of: global cognitive function; memory (general, long-term verbal recognition, long-term verbal recall); and executive function (general, shifting, updating, inhibition, generativity, fluid reasoning). There was a significant effect of sleep on global cognitive function, long-term verbal recall, long-term verbal recognition, shifting, updating, generativity, and fluid reasoning. Although there are effects on memory and executive function associated with poor sleep in PD, the effects were driven by a small number of studies. Numerous methodological issues were identified. Further studies are needed reliably to determine whether disturbed sleep impacts on cognition via mechanisms of hypoxia, hypercapnia, sleep fragmentation, chronic sleep debt or decreased REM and/or slow wave sleep in PD, as this may have important clinical implications.