Graft ischemia post cell transplantation to the brain: Glucose deprivation as the primary driver of rapid cell death.

Replacing cells lost during the progression of neurodegenerative disorders holds potential as a therapeutic strategy. Unfortunately, the majority of cells die post-transplantation, which creates logistical and biological challenges for cell therapy approaches. The cause of cell death is likely to be multifactorial in nature but has previously been correlated with hypoxia in the graft core.

Cardiac dysfunction in dialysing adults with end-stage kidney disease is associated with exercise intolerance: A pilot observational study.

People with end-stage kidney disease (ESKD) often exhibit impaired cardiac structure and function, which may contribute to poor exercise capacity. This study used multimodal exercise testing to investigate the central and peripheral mechanisms of exercise limitation in adults with ESKD, also comparing in-centre hemodialysis (ICHD) to home hemodialysis (HHD). Seventeen adults (55.

Adherence to Parkinson's disease medication: A case study to illustrate reasons for non-adherence, implications for practice and engaging under-represented participants in research.

Parkinson's disease (PD) is a progressive neurodegenerative disease which primarily presents with the core symptoms of rigidity, postural instability, tremor, and bradykinesia. Non-adherence to prescribed PD treatments can have significant ramifications, such as poor symptom control and greater disease burden. Reasons for poor adherence are multifaceted, particularly when medication regimens are complex and often based on perceptual and practical barriers.

Searching for information about stem cells online in an age of artificial intelligence: How should the stem cell community respond?

Patients and their families routinely use the Internet to learn about stem cell research. What they find, is increasingly influenced by ongoing changes in how information is filtered and presented online. This article reflects on recent developments in generative artificial intelligence and how the stem cell community should respond.

Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development.

Dysregulated cholesterol metabolism has been linked to neurodegeneration. We previously found that free, non-esterified, 7α,(25)26-dihydroxycholesterol (7α,26-diHC), was significantly elevated in the cerebrospinal fluid of patients with Parkinson's disease (PD). In this study we investigated the role of 7α,26-diHC in midbrain dopamine (mDA) neuron development and survival.

Impaired cognitive and motor function are coincident with L-DOPA-induced dyskinesia in a model of Parkinson's disease.

Dopamine transmission has been implicated in motor and cognitive function. In Parkinson's disease (PD), dopamine replacement using the precursor drug L-DOPA is the predominant treatment approach, but long-term exposure leads to the onset of dyskinesias (LIDs). Chronic L-DOPA exposure has been associated with changes in gene expression and altered cortico-striatal plasticity.

PINK1-Dependent Mitophagy Inhibits Elevated Ubiquitin Phosphorylation Caused by Mitochondrial Damage.

Ubiquitin phosphorylation by the mitochondrial protein kinase PTEN-induced kinase 1 (PINK1), upon mitochondrial depolarization, is an important intermediate step in the recycling of damaged mitochondria via mitophagy. As mutations in PINK1 can cause early-onset Parkinson's disease (PD), there has been a growing interest in small-molecule activators of PINK1-mediated mitophagy as potential PD treatments. Herein, we show that -substituted adenosines, such as -(2-furanylmethyl)adenosine (known as kinetin riboside) and -benzyladenosine, activate PINK1 in HeLa cells and induce PINK1-dependent mitophagy in primary mouse fibroblasts.

Kinetic and Chemical Effects of Clays and Other Fillers in the Preparation of Epoxy-Vinyl Ether Composites Using Radical-Induced Cationic Frontal Polymerization.

Addition of fillers to formulations can generate composites with improved mechanical properties and lower the overall cost through a reduction of chemicals needed. In this study, fillers were added to resin systems consisting of epoxies and vinyl ethers that frontally polymerized through a radical-induced cationic frontal polymerization (RICFP) mechanism. Different clays, along with inert fumed silica, were added to increase the viscosity and reduce the convection, results of which did not follow many trends present in free-radical frontal polymerization.

Cognitive trajectories during the menopausal transition.

Aims: Female sex is associated with an increased prevalence of dementia. Menopause may have a role to play in explaining sex differences in cognition, and possibly the risk of future dementia. We aimed to determine if the rate of cognitive decline differed between stages of the menopausal transition.

More than a participant in trials of cell and gene therapy: Hearing the voices of people living with neurodegenerative diseases.

With the advent of novel advanced therapy medicinal products (ATMPs) for neurodegenerative diseases, their pathway to clinical trials and the therapeutic landscape has highlighted some new challenges, many of which are outlined in other chapters of this volume. The practical considerations of all these aspects from basic research and animal models through to clinical trials and eventual clinical implementation are significant. By and large, the major voices surrounding these challenges are the scientists and clinical teams who both develop the interventions and design and deliver the clinical trials to test these novel ATMPs.

Defining the unknowns for cell therapies in Parkinson's disease.

First-in-human clinical trials have commenced to test the safety and efficacy of cell therapies for people with Parkinson's disease (PD). Proof of concept that this neural repair strategy is efficacious is based on decades of preclinical studies and clinical trials using primary foetal cells, as well as a significant literature exploring more novel stem cell-derived products. Although several measures of efficacy have been explored, including the successful in vitro differentiation of stem cells to dopamine neurons and consistent alleviation of motor dysfunction in rodent models, many unknowns still remain regarding the long-term clinical implications of this treatment strategy.

Associations of Sex, Age, and Cardiometabolic Risk Profiles With Brain Structure and Cognition: A UK Biobank Latent Class Analysis.

Background And Objectives: It is unknown whether there are sex-related profiles of cardiometabolic health that contribute differently to age-related changes in brain health during midlife. We studied how latent classes of middle-aged individuals clustering by age, sex, menopause, and cardiometabolic health were associated with brain structure and cognitive performance.

Methods: Health, brain, and abdominal MRI data from the UK Biobank cohort (men and women aged >40 years in the United Kingdom) were used.

Human Embryonic Stem Cell-Derived Dopaminergic Grafts Alleviate L-DOPA Induced Dyskinesia.

Background: First-in-human studies to test the efficacy and safety of human embryonic stem cells (hESC)-derived dopaminergic cells in the treatment of Parkinson's disease (PD) are imminent. Pre-clinical studies using hESC-derived dopamine neuron transplants in rat models have indicated that the benefits parallel those shown with fetal tissue but have thus far failed to consider how ongoing L-DOPA administration might impact on the graft.

Objective: To determine whether L-DOPA impacts on survival and functional recovery following grafting of hESC-derived dopaminergic neurons.

L-dopa-Dependent Effects of GLP-1R Agonists on the Survival of Dopaminergic Cells Transplanted into a Rat Model of Parkinson Disease.

Cell therapy is a promising treatment for Parkinson's disease (PD), however clinical trials to date have shown relatively low survival and significant patient-to-patient variability. Glucagon Like Peptide-1 receptor (GLP-1R) agonists have potential neuroprotective effects on endogenous dopaminergic neurons. This study explores whether these agents could similarly support the growth and survival of newly transplanted neurons.

Spontaneous Graft-Induced Dyskinesias Are Independent of 5-HT Neurons and Levodopa Priming in a Model of Parkinson's Disease.

Background: The risk of graft-induced dyskinesias (GIDs) presents a major challenge in progressing cell transplantation as a therapy for Parkinson's disease. Current theories implicate the presence of grafted serotonin neurons, hotspots of dopamine release, neuroinflammation and established levodopa-induced dyskinesia.

Objective: To elucidate the mechanisms of GIDs.

Factors affecting the choice of first-line therapy in Parkinson's disease patients in Wales: A population-based study.

First line treatment for Parkinson's disease (PD) is typically either L-dopa or a non-ergot dopamine agonist (DA). However, the options for the treatment of motor symptoms in PD patients have increased in the last thirty years, which have seen several new classes of PD medications introduced onto the market. The purpose of this study is to examine the changes in first line therapy of newly diagnosed Parkinson's patients between 2000 and 2016 in Wales.

Patterns and Determinants of Prescribing for Parkinson's Disease: A Systematic Literature Review.

Since the discovery of levodopa (L-dopa) in 1967, the range of medications available to treat Parkinson's disease has increased significantly and guidance on the use, efficacy, and safety of these medications has evolved. To assess levels of adherence to national prescribing guidelines and awareness of changes in the efficacy and safety data published in the profiles of medications for the treatment of PD, we have reviewed studies on patterns and determinants of prescribing PD medications conducted in the last 50 years (since the discovery of L-dopa). A systematic literature review was conducted using EMBASE (1967 to March, 2018), Ovid MEDLINE(R) ALL (1967 to March 16, 2018), PsycINFO (1967 to the 2 week of March, 2018), and PubMed to identify all studies measuring prescribing patterns of PD medication between 1967 and 2017.

L-DOPA for Parkinson's disease-a bittersweet pill.

3,4-dihydroxy-L-phenylalanine (L-DOPA) is the gold standard treatment for Parkinson's disease. It has earned that title through its highly effective treatment of some of the motor symptoms in the early stages of the disease but it is a far from perfect drug. The inevitable long-term treatment that comes with this chronic neurodegenerative condition raises the risk significantly of the development of motor fluctuations including disabling L-DOPA-induced dyskinesia.

Assessing the quality of bereavement care after perinatal death: development and piloting of a questionnaire to assess parents' experiences.

Understanding parents' experience of care is essential to develop high-quality perinatal bereavement services. This study aimed at developing a questionnaire to identify parents' needs and record their experience of care. The patient experience questionnaire was developed by professionals and parents, and piloted in a tertiary maternity unit.

Influence of chronic L-DOPA treatment on immune response following allogeneic and xenogeneic graft in a rat model of Parkinson's disease.

Although intrastriatal transplantation of fetal cells for the treatment of Parkinson's disease had shown encouraging results in initial open-label clinical trials, subsequent double-blind studies reported more debatable outcomes. These studies highlighted the need for greater preclinical analysis of the parameters that may influence the success of cell therapy. While much of this has focused on the cells and location of the transplants, few have attempted to replicate potentially critical patient centered factors.

Striatal Plasticity in L-DOPA- and Graft-Induced Dyskinesia; The Common Link?

One of the major symptoms of the neurodegenerative condition Parkinson's disease (PD) is a slowness or loss of voluntary movement, yet frustratingly therapeutic strategies designed to restore movement can result in the development of excessive abnormal movements known as dyskinesia. These dyskinesias commonly develop as a result of pharmacotherapy in the form of L-DOPA administration, but have also been identified following deep brain stimulation (DBS) and intrastriatal cell transplantation. In the case of L-DOPA these movements can be treatment limiting, and whilst they are not long lasting or troubling following DBS, recognition of their development had a near devastating effect on the field of cell transplantation for PD.