Cholinergic system changes in Parkinson's disease: emerging therapeutic approaches

In patients with Parkinson's disease, heterogeneous cholinergic system changes can occur in different brain regions. These changes correlate with a range of clinical features, both motor and non-motor, that are refractory to dopaminergic therapy, and can be conceptualised within a systems-level framework in which nodal deficits can produce circuit dysfunctions. The topographies of cholinergic changes overlap with neural circuitries involved in sleep and cognitive, motor, visuo-auditory perceptual, and autonomic functions. Cholinergic deficits within cognition network hubs predict cognitive deficits better than do total brain cholinergic changes. Postural instability and gait difficulties are associated with cholinergic system changes in thalamic, caudate, limbic, neocortical, and cerebellar nodes. Cholinergic system deficits can involve also peripheral organs. Hypercholinergic activity of mesopontine cholinergic neurons in people with isolated rapid eye movement (REM) sleep behaviour disorder, as well as in the hippocampi of cognitively normal patients with Parkinson's disease, suggests early compensation during the prodromal and early stages of Parkinson's disease. Novel pharmacological and neurostimulation approaches could target the cholinergic system to treat motor and non-motor features of Parkinson's disease

Investigative approach to improve hot water system hydraulics through temperature monitoring to reduce building environmental quality hazard associated to Legionella

Several countries have promulgated control measures and design guidelines to limit the proliferation of Legionella within hot water distribution systems (HWDS). However, there is little information on how to assess and improve existing HWDS unable to maintain water temperatures >= 55 degrees C throughout the system. A 50-year old hot water system of a 10 story hospital was investigated in terms of temperature distribution and Legionella pneumophila prevalence. Concentrations of L. pneumophila were correlated with the maximum temperature reached at the tap, with a significant decrease observed at T >= 55 degrees C. Continuous temperature and flow monitoring was performed on the overall HWDS, characterizing the principal and secondary horizontal return loops for all 9 wings, and detailed investigations of the secondary vertical return loops was completed in Wing 3. Results indicated the system inability to systematically maintain desired operating temperatures of 55 degrees C. The deficient hydraulic distribution was the root cause of the poor temperature maintenance throughout the secondary loops, but defective devices were also identified as playing an important role in sectorial temperature failure. A simple stepwise investigative approach was developed to identify hydraulic deficiencies. The implementation of flow restrictions on identified recirculation loops and increased pumping efficiency was conducted within a short period of 2 months, with no major system upgrade. These corrective measures resulted in a balanced system with increased flow velocities (>0.2 m/s). As a result, the proportion of taps achieving 55 degrees C within 2 min increased from 11% to 74% and L. pneumophila prevalence decreased from 93.1% to 46.1% after 4 weeks. (C) 2016 The Authors. Published by Elsevier Ltd

Mapping neurotransmitter systems to the structural and functional organization of the human neocortex

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.</p

FEOBV-PET to quantify cortical cholinergic denervation in AD: Relationship to basal forebrain volumetry

[Background and Purpose] Fluorine-18-fluoroethoxybenzovesamicol([18F]-FEOBV) is a PET radiotracer previously used in neurodegenerative diseases to quantify brain cholinergic denervation. The current exploratory study aimed at verifying the reliability of such an approach in Alzheimer's disease (AD) by demonstrating its concordance with MRI volumetry of the cholinergic basal forebrain (ChBF).[Methods] The sample included 12 participants evenly divided between healthy volunteers and patients with AD. All participants underwent MRI ChBF volumetry and PET imaging with [18F]-FEOBV. Comparisons were made between the two groups, and partial correlations were performed in the AD patients between [18F]-FEOBV uptake in specific cortical regions of interest (ROIs) and volumetry of the corresponding ChBF subareas, which include the nucleus basalis of Meynert (Ch4), and the medial septum/vertical limb of the diagonal band of Broca (Ch1/2).[Results] Patients with AD showed both lower ChBF-Ch4 volumetric values and lower [18F]-FEOBV cortical uptake than healthy volunteers. Volumes of the Ch4 subdivision were significantly correlated with the [18F]-FEOBV uptake values observed in the relevant ROIs. Volumes of the Ch1/2, which remains relatively unaffected in AD, did not correlate with [18F]-FEOBV uptake in the hippocampus, nor in any cortical area.[Conclusion] These results suggest that cortical cholinergic denervation as measured with [18F]-FEOBV PET is proportional to ChBF atrophy measured by MRI-based volumetry, further supporting the reliability and validity of [18F]-FEOBV PET to quantify cholinergic degeneration in AD.his research was supported by the Fonds de la recherche en santé du Québec (FRSQ).Peer reviewe

Mapping neurotransmitter systems to the structural and functional organization of the human neocortex.

Funder: Helmholts International BigBrain Analytics &amp; Learning LaboratoryNeurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.For the Cambridge authors (Coles, Fryer & Aigbirhio): This work was funded by an MRC PET Neuroscience programme grant (Training and Novel Probes Programme in PET Neurochemistry - MR/K02308X/1) and by an MRC Developmental Pathway Funding Scheme grant (MR/L013215/1). This research in Cambridge was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. JPC was supported by a British Journal of Anaesthesia/Royal College of Anaesthetists grant from the National Institute of Academic Anaesthesia