Double Blind Peer-Review in Games

Pre-publication peer-review forms the basis for how scholarly journals assess whether an articleis suitable for publication. [...

Managing cognition in progressive supranuclear palsy

Cognitive impairment is integral to the syndrome of progressive supranuclear palsy. It is most commonly described as a frontal dysexecutive syndrome but other impairments include apathy, impulsivity, visuospatial and memory functions. Cognitive dysfunction may be exacerbated by mood disturbance, medication and communication problems. In this review we advocate an individualized approach to managing cognitive impairment in progressive supranuclear palsy with the education of caregivers as a central component. Specific cognitive and behavioral treatments are complemented by treatment of mood disturbances, rationalizing medications and a patient-centered approach to communication. This aims to improve patients' quality of life, reduce carer burden and assist people with progressive supranuclear palsy in decisions about their life and health, including discussions of feeding and end-of-life issues.This work was funded by the Medical Research Council (G1100464 to T Rittman) the Wellcome Trust (103838 to JB Rowe), the NIHR-Cambridge Biomedical Research Centre and the Beverley Sackler fellowship scheme (T Rittman, ITS Coyle-Gilchrist)

Progressive supranuclear palsy: diagnosis and management.

Treating patients with progressive supranuclear palsy (PSP) is both effective and rewarding. This review aims to share our experience in the proactive management of PSP, considering the patient, the family and the medical context in which the illness unfolds. There are many opportunities to assist your patients, ameliorate their symptoms, reduce their risks and harm, and guide them through the complex medical, social and legal minefield that characterises life with chronic neurological illness. We summarise the challenges of early diagnosis, consider PSP mimics and the role of investigations in excluding these, and discuss the available pharmacological and non-pharmacological treatment strategies to tackle the common and challenging symptoms of PSP. The best treatment will be patient centred and as part of a multidisciplinary team

Neurological update: neuroimaging in dementia

Abstract: Neuroimaging for dementia has made remarkable progress in recent years, shedding light on diagnostic subtypes of dementia, predicting prognosis and monitoring pathology. This review covers some updates in the understanding of dementia using structural imaging, positron emission tomography (PET), structural and functional connectivity, and using big data and artificial intelligence. Progress with neuroimaging methods allows neuropathology to be examined in vivo, providing a suite of biomarkers for understanding neurodegeneration and for application in clinical trials. In addition, we highlight quantitative susceptibility imaging as an exciting new technique that may prove to be a sensitive biomarker for a range of neurodegenerative diseases. There are challenges in translating novel imaging techniques to clinical practice, particularly in developing standard methodologies and overcoming regulatory issues. It is likely that clinicians will need to lead the way if these obstacles are to be overcome. Continued efforts applying neuroimaging to understand mechanisms of neurodegeneration and translating them to clinical practice will complete a revolution in neuroimaging

Connectivity biomarkers in neurodegenerative tauopathies

The primary tauopathies are a group of neurodegenerative diseases affecting movement and cognition. In this thesis I study Progressive Supranuclear Palsy (PSP) and the Corticobasal Syndrome (CBS), two parkinsonian disorders associated with accumulation of hyperphos- phorylated and abnormally folded tau protein. I contrast these two disorders with Parkinson’s disease (PD), which is associated with the accumulation of alpha-synuclein but has a genetic association with the MAPT gene encoding tau. Understanding the tauopathies to develop effective treatments will require a better grasp of the relationships between clinical syndromes and cognitive measures and how the anatomical and neurochemical networks that underlie clinical features might be altered by disease. I investigate simple clinical biomarkers, showing that a two-minute test of verbal fluency is a potential diagnostic biomarker to distinguish between PD and PSP and that the ACE-R and its subscores could play a role in monitoring cognition over time in PD, PSP and CBS. I assess the implementation of network analysis in Functional Mag- netic Resonance Imaging (fMRI) data, introduce Maybrain software for graphical network analysis and visualisation. I go on to show an overlap between graph theory network measures and I identify three main factors underlying graph network measures of: efficiency and distance, hub characteristics, network community measures. I apply these measures in PD, PSP and the CBS. All three diseases caused a loss of functional connectivity in com- parison to the control group that was concentrated in more highly connected brain regions and in longer distance connections. In ad- dition, widely localised cognitive function of verbal fluency co-varied with the connection strength in highly connected regions across PD, PSP and CBS. To take this further, I investigated specific functional covariance networks. All three disease groups showed reduced connectivity between the basal ganglia network and other networks, and between the anterior salience network and other networks. Localised areas of increased co- variance suggest a breakdown of network boundaries which correlated with motor severity in PSP and CBS, and duration of disease in CBS. I explore the link between gene expression of the tau gene MAPT and its effects on functional connectivity showing that the expression of MAPT correlated with connection strength in highly connected hub regions that were more susceptible to a loss of connection strength in PD and PSP. I conclude by discussing how tau protein aggregates and soluble tau oligomers may explain the changes in functional brain networks. The primary tauopathies are a group of neurodegenerative diseases affecting movement and cognition. In this thesis I study Progressive Supranuclear Palsy (PSP) and the Corticobasal Syndrome (CBS), two parkinsonian disorders associated with accumulation of hyperphos- phorylated and abnormally folded tau protein. I contrast these two disorders with Parkinson’s disease (PD), which is associated with the accumulation of alpha-synuclein but has a genetic association with the MAPT gene encoding tau. Understanding the tauopathies to develop effective treatments will require a better grasp of the relationships between clinical syndromes and cognitive measures and how the anatomical and neurochemical networks that underlie clinical features might be altered by disease. I investigate simple clinical biomarkers, showing that a two-minute test of verbal fluency is a potential diagnostic biomarker to distinguish between PD and PSP and that the ACE-R and its subscores could play a role in monitoring cognition over time in PD, PSP and CBS. I assess the implementation of network analysis in Functional Mag- netic Resonance Imaging (fMRI) data, introduce Maybrain software for graphical network analysis and visualisation. I go on to show an overlap between graph theory network measures and I identify three main factors underlying graph network measures of: efficiency and distance, hub characteristics, network community measures. I apply these measures in PD, PSP and the CBS. All three diseases caused a loss of functional connectivity in com- parison to the control group that was concentrated in more highly connected brain regions and in longer distance connections. In ad- dition, widely localised cognitive function of verbal fluency co-varied with the connection strength in highly connected regions across PD, PSP and CBS. To take this further, I investigated specific functional covariance networks. All three disease groups showed reduced connectivity between the basal ganglia network and other networks, and between the anterior salience network and other networks. Localised areas of increased co- variance suggest a breakdown of network boundaries which correlated with motor severity in PSP and CBS, and duration of disease in CBS. I explore the link between gene expression of the tau gene MAPT and its effects on functional connectivity showing that the expression of MAPT correlated with connection strength in highly connected hub regions that were more susceptible to a loss of connection strength in PD and PSP. I conclude by discussing how tau protein aggregates and soluble tau oligomers may explain the changes in functional brain networks.This work was supported by the Medical Research Council (grant number G1100464) and a Sackler Scholarshi

Reorganisation of cortical oscillatory dynamics underlying disinhibition in frontotemporal dementia

The distribution of pathology in frontotemporal dementia is anatomically selective, to distinct cortical regions and with differential neurodegeneration across the cortical layers. The cytoarchitecture and connectivity of cortical laminae preferentially supports frequency-specific oscillations and hierarchical information transfer between brain regions. We therefore predicted that in frontotemporal dementia, core functional deficits such as disinhibition would be associated with differences in the frequency spectrum and altered cross-frequency coupling between frontal cortical regions. We examined this hypothesis using a “Go-NoGo” response inhibition paradigm with eighteen patients with behavioural variant frontotemporal dementia and 20 healthy aged-matched during magnetoencephalography. During Go and NoGo trials, beta desynchronisation was severely attenuated in patients. Beta power was associated with increased impulsivity, as measured by the Cambridge Behavioural Inventory, a carer based questionnaire of changes in everyday behaviour. To quantify the changes in cross-frequency coupling in the frontal lobe, we used Dynamic Causal Modeling to test a family of hierarchical casual models, which included the inferior frontal gyrus, pre-supplementary motor area (preSMA) and primary motor cortex. This analysis revealed evidence for cross-frequency coupling in a fully connected network in both groups. However, in the patient group, we identified a significant loss of reciprocal connectivity of the inferior frontal gyrus, particularly for interactions in the gamma band and for theta to alpha coupling. Importantly, although prefrontal coupling was diminished, gamma connectivity between preSMA and motor cortex was enhanced in patients. We propose that the disruption of behavioural control arises from reduced frequency-specific connectivity of the prefrontal cortex, together with a hyper-synchronous reorganisation of connectivity among preSMA and motor regions. These results are supported by preclinical evidence of the selectivity of frontotemporal lobar degeneration on oscillatory dynamics, and provide a clinically relevant yet precise neurophysiological signature of behavioural control as a potential pharmacological target for early phase experimental medicines studies.This work was primarily funded by the Wellcome Trust (103838) with additional support from the Medical Research Council (MC-A060-5PQ30, and RG62761) and the NIHR Cambridge Biomedical Research Centre and Cambridge Brain Bank. The BCNI is supported by a joint award from the Wellcome Trust and Medical Research Council

Evolution of Sci's Community-Driven Post-Publication Peer-Review

No abstract available