Parkinson’s disease dyskinesias possibly relate to greater dopamine transporter losses in the putamen over time

The pathophysiology of levodopa-induced dyskinesias in Parkinson’s disease is incompletely understood. This study was designed to investigate in Parkinson’s patients, whether time-related changes in striatal dopamine transporter availability are associated to the appearance of dyskinesias. 15 Parkinson’s patients had dopamine transporter-specific SPECT imaging with 123I-FP-CIT twice: at baseline (when they were drug naïve) and at follow-up (6.31±2.29 years from baseline), and were followed up clinically every six months. At the end of the study, patients were divided in two groups according to whether they had developed dyskinesias or not. Semi-quantification of 123I-FP-CIT data was performed using the occipital cortex as the reference region. Specific binding ratios were calculated for the putamen and the caudate. During the clinical follow-up, all Parkinson’s patients were treated pharmaceutically. 8 patients developed dyskinesias, while 7 remained nondyskinetic. At baseline, the two groups had similar 123I-FP-CIT specific binding ratio values for the putamen and the caudate (p>0.05). Also, between-group differences in age, disease duration, and Hoehn & Yahr scores were not statistically significant. Over-time, the putaminal 123I-FP-CIT specific binding ratio values in the dyskinetic group decreased significantly (p<0.01). The nondyskinetic patients had smaller reductions (p<0.05) during the same period of time. At follow-up, the dyskinetic patients had significantly higher Hoehn & Yahr scores (p<0.01) and were taking higher levodopa equivalent doses (p<0.001), as compared to the nondyskinetic patients. The development of Parkinson’s dyskinesias is related to a faster progression rate, as reflected by marked putaminal dopamine transporter decreases

Three new potent cytotoxic macrolides closely related to sphinxolide from the New Caledonia sponge Neosiphonia superstes

Three new macrolides 2-4 have been isolated with sphinxolide 1 from the marine sponge #N. superstes$ collected off New Caledonia. The structures of the new compounds were determined by interpretation of NMR spectral data as well as comparison of spectral data with those of 1. These compounds were highly cytotoxic against various human carcinoma cells. (Résumé d'auteur

Methinks: Enabling Sophisticated Comment Management in the Social Web

User reviews, comments and votes on the Social Web form the modern version of word-of-mouth communication, which has a huge impact on people’s shopping habits, businesses and the overall market. Despite that, systems have so far limited practical success in helping consumers and businesses analysing, managing and understanding Social Web content. In this paper, we present a new tool that leverages a combination of techniques from Semantic Web, Computational Argumentation and Crowdsourcing to support this activity, through an intuitive and functional user interface

Dissociable effects of age and Parkinson’s disease on instruction-based learning

The cognitive deficits associated with Parkinson’s disease vary across individuals and change across time, with implications for prognosis and treatment. Key outstanding challenges are to define the distinct behavioural characteristics of this disorder and develop diagnostic paradigms that can assess these sensitively in individuals. In a previous study, we measured different aspects of attentional control in Parkinson’s disease using an established fMRI switching paradigm. We observed no deficits for the aspects of attention the task was designed to examine; instead those with Parkinson’s disease learnt the operational requirements of the task more slowly. We hypothesized that a subset of people with early-to-mid stage Parkinson’s might be impaired when encoding rules for performing new tasks. Here, we directly test this hypothesis and investigate whether deficits in instruction-based learning represent a characteristic of Parkinson’s Disease. Seventeen participants with Parkinson’s disease (8 male; mean age: 61.2 years), 18 older adults (8 male; mean age: 61.3 years) and 20 younger adults (10 males; mean age: 26.7 years) undertook a simple instruction-based learning paradigm in the MRI scanner. They sorted sequences of coloured shapes according to binary discrimination rules that were updated at two-minute intervals. Unlike common reinforcement learning tasks, the rules were unambiguous, being explicitly presented; consequently, there was no requirement to monitor feedback or estimate contingencies. Despite its simplicity, a third of the Parkinson’s group, but only one older adult, showed marked increases in errors, 4 SD greater than the worst performing young adult. The pattern of errors was consistent, reflecting a tendency to misbind discrimination rules. The misbinding behaviour was coupled with reduced frontal, parietal and anterior caudate activity when rules were being encoded, but not when attention was initially oriented to the instruction slides or when discrimination trials were performed. Concomitantly, Magnetic Resonance Spectroscopy showed reduced gamma-Aminobutyric acid levels within the mid-dorsolateral prefrontal cortices of individuals who made misbinding errors. These results demonstrate, for the first time, that a subset of early-to-mid stage people with Parkinson’s show substantial deficits when binding new task rules in working memory. Given the ubiquity of instruction-based learning, these deficits are likely to impede daily living. They will also confound clinical assessment of other cognitive processes. Future work should determine the value of instruction-based learning as a sensitive early marker of cognitive decline and as a measure of responsiveness to therapy in Parkinson's disease

Relationship between neuromelanin and dopamine terminals within the Parkinson's nigrostriatal system.

Parkinson's disease is characterized by the progressive loss of pigmented dopaminergic neurons in the substantia nigra and associated striatal deafferentation. Neuromelanin content is thought to reflect the loss of pigmented neurons, but available data characterizing its relationship with striatal dopaminergic integrity are not comprehensive or consistent, and predominantly involve heterogeneous samples. In this cross-sectional study, we used neuromelanin-sensitive MRI and the highly specific dopamine transporter PET radioligand, 11C-PE2I, to assess the association between neuromelanin-containing cell levels in the substantia nigra pars compacta and nigrostriatal terminal density in vivo, in 30 patients with bilateral Parkinson's disease. Fifteen healthy control subjects also underwent neuromelanin-sensitive imaging. We used a novel approach taking into account the anatomical and functional subdivision of substantia nigra into dorsal and ventral tiers and striatal nuclei into pre- and post-commissural subregions, in accordance with previous animal and post-mortem studies, and consider the clinically asymmetric disease presentation. In vivo, Parkinson's disease subjects displayed reduced neuromelanin levels in the ventral (-30 ± 28%) and dorsal tiers (-21 ± 24%) as compared to the control group [F(1,43) = 11.95, P = 0.001]. Within the Parkinson's disease group, nigral pigmentation was lower in the ventral tier as compared to the dorsal tier [F(1,29) = 36.19, P < 0.001] and lower in the clinically-defined most affected side [F(1,29) = 4.85, P = 0.036]. Similarly, lower dopamine transporter density was observed in the ventral tier [F(1,29) = 76.39, P < 0.001] and clinically-defined most affected side [F(1,29) = 4.21, P = 0.049]. Despite similar patterns, regression analysis showed no significant association between nigral pigmentation and nigral dopamine transporter density. However, for the clinically-defined most affected side, significant relationships were observed between pigmentation of the ventral nigral tier with striatal dopamine transporter binding in pre-commissural and post-commissural striatal subregions known to receive nigrostriatal projections from this tier, while the dorsal tier correlated with striatal projection sites in the pre-commissural striatum (P < 0.05, Benjamini-Hochberg corrected). In contrast, there were no statistically significant relationships between these two measures in the clinically-defined least affected side. These findings provide important insights into the topography of nigrostriatal neurodegeneration in Parkinson's disease, indicating that the characteristics of disease progression may fundamentally differ across hemispheres and support post-mortem data showing asynchrony in the loss of neuromelanin-containing versus tyrosine hydroxylase positive nigral cells.The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) [FP7-242003], from the Medical Research Council (MRC) [MR/P025870/1] and from Parkinson’s UK [J-1204]. Infrastructure support for this research was provided by the NIHR Imperial Biomedical Research Centre (BRC) and NIHR Imperial CRF at Imperial College healthcare NHS trust. The views expressed are those of the authors and not necessarily those of the funder, the NHS, the NIHR, or the Department of Health. This work was also supported financially by a PhD studentship awarded to N.P.L-K from Parkinson’s UK

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. 11C-PE2I 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