G-Force PD: a global initiative in coordinating stem cell-based dopamine treatments for Parkinson's disease.

Translating new cell-based therapies to the clinic for patients with neurodegenerative disorders is complex. It involves pre-clinical testing of the cellular product and discussions with several regulatory agencies, as well as ethical debates. In an attempt to support efforts around the world, we set up a global consortium that brings together the major funded teams working on developing a stem cell-derived neural transplantation therapy for Parkinson's disease (PD). This consortium, G-Force PD, involves teams from Europe, USA, and Japan, and has already met on two occasions to discuss common problems, solutions, and the roadmap to the clinic. In this short review, we lay out the brief history and rationale for this initiative and discuss some of the issues that arose in our most recent meeting (May 2015) as we consider undertaking first-in-human clinical trials with stem cell-derived neurons for PD.We would like to thank all the respective funding agencies that support our work in this area including the EU FP7 programmes that fund TRANSEURO (HEALTH-F5-2010-242003) and Neurostemcellrepair (HEALTH-2013-INNOVATION-1-602278), NYSTEM (C028503) that supports the work of Studer et al, and a grant from the Network Program for Realization of Regenerative Medicine from the Japan Agency for Medical Research and Development (AMED) that supports the work of Takahashi et al. We would also like to thank Parkinson’s UK for help funding the first GForce-PD meeting in London and the Parkinson’s Disease Foundation (PDF) and Weill Cornell for the second in New York.This is the final version of the article. It first appeared from NPG via http://dx.doi.org/10.1038/npjparkd.2015.1

Evolution of a Complex Locus: Exon Gain, Loss and Divergence at the Gr39a Locus in Drosophila

Background. Gene families typically evolve by gene duplication followed by the adoption of new or altered gene functions. A different way to evolve new but related functions is alternative splicing of existing exons of a complex gene. The chemosensory gene families of animals are characterised by numerous loci of related function. Alternative splicing has only rarely been reported in chemosensory loci, for example in 5 out of around 120 loci in Drosophila melanogaster. The gustatory receptor gene Gr39a has four large exons that are alternatively spliced with three small conserved exons. Recently the genome sequences of eleven additional species of Drosophila have become available allowing us to examine variation in the structure of the Gr39a locus across a wide phylogenetic range of fly species. Methodology/Principal Findings. We describe a fifth exon and show that the locus has a complex evolutionary history with several duplications, pseudogenisations and losses of exons. PAML analyses suggested that the whole gene has a history of purifying selection, although this was less strong in exons which underwent duplication. Conclusions/Significance. Estimates of functional divergence between exons were similar in magnitude to functional divergence between duplicated genes, suggesting that exon divergence is broadly equivalent to gene duplication.Publisher PDFPeer reviewe

Utility of the new Movement Disorder Society clinical diagnostic criteria for Parkinson's disease applied retrospectively in a large cohort study of recent onset cases

Objective: To examine the utility of the new Movement Disorder Society (MDS) diagnostic criteria in a large cohort of Parkinson's disease (PD) patients. Methods: Recently diagnosed (<3.5 years) PD cases fulfilling United Kingdom (UK) brain bank criteria in Tracking Parkinson's, a UK multicenter prospective natural history study were assessed by retrospective application of the MDS criteria. Results: In 2000 cases, 1835 (91.7%) met MDS criteria for PD, either clinically established (n = 1261, 63.1%) or clinically probable (n = 574, 28.7%), leaving 165 (8.3%) not fulfilling criteria. Clinically established cases were significantly more likely to have limb rest tremor (89.3%), a good l-dopa response (79.5%), and olfactory loss (71.1%), than clinically probable cases (60.6%, 44.4%, and 34.5% respectively), but differences between probable PD and ‘not PD’ cases were less evident. In cases not fulfilling criteria, the mean MDS UPDRS3 score (25.1, SD 13.2) was significantly higher than in probable PD (22.3, SD 12.7, p = 0.016) but not established PD (22.9, SD 12.0, p = 0.066). The l-dopa equivalent daily dose of 341 mg (SD 261) in non-PD cases was significantly higher than in probable PD (250 mg, SD 214, p < 0.001) and established PD (308 mg, SD 199, p = 0.025). After 30 months' follow-up, 89.5% of clinically established cases at baseline remained as PD (established/probable), and 86.9% of those categorized as clinically probable at baseline remained as PD (established/probable). Cases not fulfilling PD criteria had more severe parkinsonism, in particular relating to postural instability, gait problems, and cognitive impairment. Conclusion: Over 90% of cases clinically diagnosed as early PD fulfilled the MDS criteria for PD. Those not fulfilling criteria may have an atypical parkinsonian disorder or secondary parkinsonism that is not correctly identified by the UK Brain Bank criteria, but possibly by the new criteria

Using Medical Claims Analyses to Understand Interventions for Parkinson Patients.

The scientific evidence to support the value of a range of non-pharmacological interventions for people with Parkinson's disease (PD) is increasing. However, showing unequivocally that specific interventions are better than usual care is not straightforward because of generic drawbacks of clinical trials. Here, we address these challenges, specifically related to the context of evaluating complex non-pharmacological interventions for people with PD. Moreover, we discuss the potential merits of undertaking "real world" analyses using medical claims data. We illustrate this approach by discussing an interesting recent publication in The Lancet Neurology, which used such an approach to demonstrate the value of specialized physiotherapy for PD patients, over and above usual care physiotherapy.Professor Bastiaan R. Bloem is supported by a research grant of the Parkinson’s Foundation. Dr. Nienke M. de Vries is supported by a research grant from The Netherlands Organization for Health Research and Development. Dr. Allison Willis is supported by the Parkinson’s Foundation, the National Institutes of Health (R01-NS-099129-01A1), the Patient Centred Outcomes Research Institute, and the University of Pennsylvania

Vascular disease and vascular risk factors in relation to motor features and cognition in early Parkinson's disease

Funded by Parkinson's UK National Institute for Health Research (NIHR) DeNDRoN network NIHR Newcastle Biomedical Research Unit Newcastle University NIHR funded Biomedical Research Centre in CambridgePeer reviewedPublisher PD

The role of tau in the pathological process and clinical expression of Huntington's disease.

Huntington's disease is a neurodegenerative disorder caused by an abnormal CAG repeat expansion within exon 1 of the huntingtin gene HTT. While several genetic modifiers, distinct from the Huntington's disease locus itself, have been identified as being linked to the clinical expression and progression of Huntington's disease, the exact molecular mechanisms driving its pathogenic cascade and clinical features, especially the dementia, are not fully understood. Recently the microtubule associated protein tau, MAPT, which is associated with several neurodegenerative disorders, has been implicated in Huntington's disease. We explored this association in more detail at the neuropathological, genetic and clinical level. We first investigated tau pathology by looking for the presence of hyperphosphorylated tau aggregates, co-localization of tau with mutant HTT and its oligomeric intermediates in post-mortem brain samples from patients with Huntington's disease (n = 16) compared to cases with a known tauopathy and healthy controls. Next, we undertook a genotype-phenotype analysis of a large cohort of patients with Huntington's disease (n = 960) with a particular focus on cognitive decline. We report not only on the tau pathology in the Huntington's disease brain but also the association between genetic variation in tau gene and the clinical expression and progression of the disease. We found extensive pathological inclusions containing abnormally phosphorylated tau protein that co-localized in some instances with mutant HTT. We confirmed this related to the disease process rather than age, by showing it is also present in two patients with young-onset Huntington's disease (26 and 40 years old at death). In addition we demonstrate that tau oligomers (suggested to be the most likely neurotoxic tau entity) are present in the Huntington's disease brains. Finally we highlight the clinical significance of this pathology by demonstrating that the MAPT haplotypes affect the rate of cognitive decline in a large cohort of patients with Huntington's disease. Our findings therefore highlight a novel important role of tau in the pathogenic process and clinical expression of Huntington's disease, which in turn opens up new therapeutic avenues for this incurable condition.The authors thank the EHDN REGISTRY Study Group investigators (listed in the Supplementary material) for collecting the data and all participating REGISTRY patients for their time and efforts, the Cambridge Brain Bank for the post-mortem tissue which is supported by a grant to the NIHR Cambridge Biomedical Research Centre and in particular to J. Wilson and Dr D. O’ Donovan. We are grateful to S. Sawcer and M. Ban in the Neurology Unit at the University of Cambridge, for their help with the genotyping, C.H. Williams-Gray at the John van Geest Centre for Brain Repair, University of Cambridge, for her help with the statistical analyses, J. Hardy, J.L. Holton, and T. Revesz at the UCL Institute of Neurology for their helpful discussions as well as K. Strand, F. Javad and A. Posada Bórbon, at the UCL Institute of Neurology, for their support with the experimental work, R. Kayed at the University of Texas Medical Branch, Galveston, for providing the TOMA and T22 antibodies. Finally, P. Tyers, R. Raha-Chowdhury, A. Tolkovsky, B. Ossola and J. Simpson for their support and encouragement throughout this work.This is the final version of the article. It was first available from Oxford University Press viahttp://dx.doi.org/10.1093/brain/awv10

L-dopa responsiveness in early Parkinson's disease is associated with the rate of motor progression.

BACKGROUND: L-dopa responsiveness in Parkinson's disease (PD) varies, but the clinical correlates and significance of this are ill-defined. METHODS: Patients were assessed before and after their usual morning L-dopa dose, using the MDS Unified PD Rating Scale Part 3 (MDS UPDRS 3), and rated as definite responders (≥24.5% improvement) or limited responders (<24.5%). RESULTS: 1007 cases, mean age 66.1 years (SD 9.1) at diagnosis, were assessed 3.4 (SD 0.9) years after diagnosis. The L-dopa response was definite in 614 cases (61.0%), median reduction in MDS UPDRS 3 scores was 42.0%, (IQR 33.3, 53.1), and was limited in 393 cases (39.0%), median reduction in MDS UPDRS 3 scores 11.5% (IQR 4.3, 18.2). Definite responders were younger (66.3 years at study entry, SD 9.3) than limited responders (69.2 years, SD 8.4, p < 0.001). The MDS UPDRS 3 score at study entry in definite responders (21.0, SD 10.5) was significantly lower than in limited responders (24.7, SD 13.4, p < 0.001). The MDS UPDRS 3 increase over 18 months was less in definite responders at 3.0 (SD 10.4), compared to limited responders (6.4, SD 11.0, p < 0.001). The levodopa equivalent daily dose (LEDD) was not significantly different at study entry (definite responders 317 mg, SD 199, vs limited responders 305 mg, SD 191, p = 0.53). However, LEDD was significantly higher at the time of the L-dopa challenge test in definite responders (541 mg, SD 293) compared to limited responders (485 mg, SD 215, p = 0.01). Responsiveness to L-dopa was unaffected by the challenge test dose (p = 0.54). CONCLUSIONS: The main determinants of variation in the L-dopa response in early PD are age and motor severity. A limited L-dopa response is associated with faster motor progression

Altered subcortical emotional salience processing differentiates Parkinson’s patients with and without psychotic symptoms

Objective Current research does not provide a clear explanation for why some patients with Parkinson’s Disease (PD) develop psychotic symptoms. The ‘aberrant salience hypothesis’ of psychosis has been influential and proposes that dopaminergic dysregulation leads to inappropriate attribution of salience to irrelevant/non-informative stimuli, facilitating the formation of hallucinations and delusions. The aim of this study is to investigate whether non-motivational salience is altered in PD patients and possibly linked to the development of psychotic symptoms. Methods We investigated salience processing in 14 PD patients with psychotic symptoms, 23 PD patients without psychotic symptoms and 19 healthy controls. All patients were on dopaminergic medication for their PD. We examined emotional salience using a visual oddball fMRI paradigm that has been used to investigate early stages of schizophrenia spectrum psychosis, controlling for resting cerebral blood flow as assessed with arterial spin labelling fMRI. Results We found significant differences between patient groups in brain responses to emotional salience. PD patients with psychotic symptoms had enhanced brain responses in the striatum, dopaminergic midbrain, hippocampus and amygdala compared to patients without psychotic symptoms. PD patients with psychotic symptoms showed significant correlations between the levels of dopaminergic drugs they were taking and BOLD signalling, as well as psychotic symptom scores. Conclusion Our study suggests that enhanced signalling in the striatum, dopaminergic midbrain, the hippocampus and amygdala is associated with the development of psychotic symptoms in PD, in line with that proposed in the ‘aberrant salience hypothesis’ of psychosis in schizophrenia

The translation, validity and reliability of the German version of the Fremantle Back Awareness Questionnaire

Background: The Fremantle Back Awareness Questionnaire (FreBAQ) claims to assess disrupted self-perception of the back. The aim of this study was to develop a German version of the Fre-BAQ (FreBAQ-G) and assess its test-retest reliability, its known-groups validity and its convergent validity with another purported measure of back perception. Methods: The FreBaQ-G was translated following international guidelines for the transcultural adaptation of questionnaires. Thirty-five patients with non-specific CLBP and 48 healthy participants were recruited. Assessor one administered the FreBAQ-G to each patient with CLBP on two separate days to quantify intra-observer reliability. Assessor two administered the FreBaQ-G to each patient on day 1. The scores were compared to those obtained by assessor one on day 1 to assess inter-observer reliability. Known-groups validity was quantified by comparing the FreBAQ-G score between patients and healthy controls. To assess convergent validity, patient\u27s FreBAQ-G scores were correlated to their two-point discrimination (TPD) scores. Results: Intra- and Inter-observer reliability were both moderate with ICC3.1 = 0.88 (95%CI: 0.77 to 0.94) and 0.89 (95%CI: 0.79 to 0.94), respectively. Intra- and inter-observer limits of agreement (LoA) were 6.2 (95%CI: 5.0±8.1) and 6.0 (4.8±7.8), respectively. The adjusted mean difference between patients and controls was 5.4 (95%CI: 3.0 to 7.8, p\u3c0.01). Patient\u27s FreBAQ-G scores were not associated with TPD thresholds (Pearson\u27s r = -0.05, p = 0.79). Conclusions: The FreBAQ-G demonstrated a degree of reliability and known-groups validity. Interpretation of patient level data should be performed with caution because the LoA were substantial. It did not demonstrate convergent validity against TPD. Floor effects of some items of the FreBAQ-G may have influenced the validity and reliability results. The clinimetric properties of the FreBAQ-G require further investigation as a simple measure of disrupted self-perception of the back before firm recommendations on its use can be made

Longitudinal functional connectivity changes related to dopaminergic decline in Parkinson’s disease

Background: Resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated that basal ganglia functional connectivity is altered in Parkinson’s disease (PD) as compared to healthy controls. However, such functional connectivity alterations have not been related to the dopaminergic deficits that occurs in PD over time. Objectives: To examine whether functional connectivity impairments are correlated with dopaminergic deficits across basal ganglia subdivisions in patients with PD both cross-sectionally and longitudinally. Methods: We assessed resting-state functional connectivity of basal ganglia subdivisions and dopamine transporter density using 11C-PE2I PET in thirty-four PD patients at baseline. Of these, twenty PD patients were rescanned after 19.9 ± 3.8 months. A seed-based approach was used to analyze resting-state fMRI data. 11CPE2I binding potential (BPND) was calculated for each participant. PD patients were assessed for disease severity. Results: At baseline, PD patients with greater dopaminergic deficits, as measured with 11C-PE2I PET, showed larger decreases in posterior putamen functional connectivity with the midbrain and pallidum. Reduced functional connectivity of the posterior putamen with the thalamus, midbrain, supplementary motor area and sensorimotor cortex over time were significantly associated with changes in DAT density over the same period. Furthermore, increased motor disability was associated with lower intraregional functional connectivity of the posterior putamen. Conclusions: Our findings suggest that basal ganglia functional connectivity is related to integrity of dopaminergic system in patients with PD. Application of resting-state fMRI in a large cohort and longitudinal scanning may be a powerful tool for assessing underlying PD pathology and its progression