Reduced LRRK2 in association with retromer dysfunction in post-mortem brain tissue from LRRK2 mutation carriers

Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are pathogenic for familial Parkinson's disease. However, it is unknown whether levels of LRRK2 protein in the brain are altered in patients with LRRK2-associated Parkinson's disease. Because LRRK2 mutations are relatively rare, accounting for approximately 1% of all Parkinson's disease, we accessioned cases from five international brain banks to investigate levels of the LRRK2 protein, and other genetically associated Parkinson's disease proteins. Brain tissue was obtained from 17 LRRK2 mutation carriers (12 with the G2019S mutation and five with the I2020T mutation) and assayed by immunoblot. Compared to matched controls and idiopathic Parkinson's disease cases, we found levels of LRRK2 protein were reduced in the LRRK2 mutation cases. We also measured a decrease in two other proteins genetically implicated in Parkinson's disease, the core retromer component, vacuolar protein sorting associated protein 35 (VPS35), and the lysosomal hydrolase, glucocerebrosidase (GBA). Moreover, the classical retromer cargo protein, cation-independent mannose-6-phosphate receptor (MPR300, encoded by IGF2R), was also reduced in the LRRK2 mutation cohort and protein levels of the receptor were correlated to levels of LRRK2. These results provide new data on LRRK2 protein expression in brain tissue from LRRK2 mutation carriers and support a relationship between LRRK2 and retromer dysfunction in LRRK2-associated Parkinson's disease brain

Land Use Change to Reduce Freshwater Nitrogen and Phosphorus will Be Effective Even with Projected Climate Change

Recent studies have demonstrated that projected climate change will likely enhance nitrogen (N) and phosphorus (P) loss from farms and farmland, with the potential to worsen freshwater eutrophication. Here, we investigate the relative importance of the climate and land use drivers of nutrient loss in nine study catchments in Europe and a neighboring country (Turkey), ranging in area from 50 to 12,000 km2. The aim was to quantify whether planned large-scale, land use change aimed at N and P loss reduction would be effective given projected climate change. To this end, catchment-scale biophysical models were applied within a common framework to quantify the integrated effects of projected changes in climate, land use (including wastewater inputs), N deposition, and water use on river and lake water quantity and quality for the mid-21st century. The proposed land use changes were derived from catchment stakeholder workshops, and the assessment quantified changes in mean annual N and P concentrations and loads. At most of the sites, the projected effects of climate change alone on nutrient concentrations and loads were small, whilst land use changes had a larger effect and were of sufficient magnitude that, overall, a move to more environmentally focused farming achieved a reduction in N and P concentrations and loads despite projected climate change. However, at Beyşehir lake in Turkey, increased temperatures and lower precipitation reduced water flows considerably, making climate change, rather than more intensive nutrient usage, the greatest threat to the freshwater ecosystem. Individual site responses did however vary and were dependent on the balance of diffuse and point source inputs. Simulated lake chlorophyll-a changes were not generally proportional to changes in nutrient loading. Further work is required to accurately simulate the flow and water quality extremes and determine how reductions in freshwater N and P translate into an aquatic ecosystem response

Epidemiological Pathology of Dementia: Attributable-Risks at Death in the Medical Research Council Cognitive Function and Ageing Study

Researchers from the Medical Research Council Cognitive Function and Ageing Neuropathology Study carry out an analysis of brain pathologies contributing to dementia, within a cohort of elderly individuals in the UK who agreed to brain donation

Basic notions of information structure

This article takes stock of the basic notions of Information Structure (IS). It first provides a general characterization of IS — following Chafe (1976) — within a communicative model of Common Ground(CG), which distinguishes between CG content and CG management. IS is concerned with those features of language that concern the local CG. Second, this paper defines and discusses the notions of Focus (as indicating alternatives) and its various uses, Givenness (as indicating that a denotation is already present in the CG), and Topic (as specifying what a statement is about). It also proposes a new notion, Delimitation, which comprises contrastive topics and frame setters, and indicates that the current conversational move does not entirely satisfy the local communicative needs. It also points out that rhetorical structuring partly belongs to IS.Peer Reviewe

The management and outcome for patients with chronic subdural hematoma: a prospective, multicenter, observational cohort study in the United Kingdom

Symptomatic chronic subdural hematoma (CSDH) will become an increasingly common presentation in neurosurgical practice as the population ages, but quality evidence is still lacking to guide the optimal management for these patients. The British Neurosurgical Trainee Research Collaborative (BNTRC) was established by neurosurgical trainees in 2012 to improve research by combining the efforts of trainees in each of the United Kingdom (UK) and Ireland's neurosurgical units (NSUs). The authors present the first study by the BNTRC that describes current management and outcomes for patients with CSDH throughout the UK and Ireland. This provides a resource both for current clinical practice and future clinical research on CSDH

Elevated Pontine and Putamenal GABA Levels in Mild-Moderate Parkinson Disease Detected by 7 Tesla Proton MRS

Background: Parkinson disease (PD) is characterized by the degeneration of nigrostriatal dopaminergic neurons. However, postmortem evidence indicates that the pathology of lower brainstem regions, such as the pons and medulla, precedes nigral involvement. Consistently, pontomedullary damage was implicated by structural and PET imaging in early PD. Neurochemical correlates of this early pathological involvement in PD are unknown. Methodology/Principal Finding: To map biochemical alterations in the brains of individuals with mild-moderate PD we quantified neurochemical profiles of the pons, putamen and substantia nigra by 7 tesla (T) proton magnetic resonance spectroscopy. Thirteen individuals with idiopathic PD (Hoehn & Yahr stage 2) and 12 age- and gender-matched healthy volunteers participated in the study. c-Aminobutyric acid (GABA) concentrations in the pons and putamen were significantly higher in patients (N = 11, off medications) than controls (N = 11, p,0.001 for pons and p,0.05 for putamen). The GABA elevation was more pronounced in the pons (64%) than in the putamen (32%). No other neurochemical differences were observed between patients and controls. Conclusion/Significance: The GABA elevation in the putamen is consistent with prior postmortem findings in patients with PD, as well as with in vivo observations in a rodent model of PD, while the GABA finding in the pons is novel. The more significant GABA elevation in the pons relative to the putamen is consistent with earlier pathological involvement of th