ORCID Profile
0000-0002-4994-0488
Current Organisations
University College London
,
The University of Sydney Faculty of Medicine and Health
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Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.NEUROBIOLAGING.2022.01.001
Abstract: Recent models of hallucinations in Lewy body disorders implicate dysfunction in 'higher order' thalamic regions involved in perceptual integration and cognitive processing. However, the degree of pathology and degeneration in these regions has not been assessed. We sought to assess atrophy, neuronal size, and neuronal numbers in the Mediodorsal (MDn) and Anterior Principal (APn) nuclei of the thalamus across Lewy body disorders comparing between patients with and without hallucinations. Postmortem tissue was acquired from 24 patients with Lewy body disease and 10 age-matched controls and analyzed using standard stereological and quantitative neuropathological techniques. Atrophy in MDn was significantly greater in patients with well-formed visual hallucinations and did not correlate significantly with neuronal size or number. Atrophy in APn was seen across all Lewy body disorders but was not significantly associated with hallucinations. α-synuclein immunoreactivity was found to be low in both the APn and MDn across all groups. These results suggest that MDn atrophy may be a marker of hallucinations and plays a role in their pathophysiology.
Publisher: Wiley
Date: 2020
DOI: 10.1002/MDS.27939
Publisher: Wiley
Date: 07-04-2021
DOI: 10.1111/JSR.13040
Publisher: Oxford University Press (OUP)
Date: 18-10-2013
DOI: 10.1093/BRAIN/AWT272
Abstract: Recent neuroimaging evidence has led to the proposal that freezing of gait in Parkinson's disease is due to dysfunctional interactions between frontoparietal cortical regions and subcortical structures, such as the striatum. However, to date, no study has employed task-based functional connectivity analyses to explore this hypothesis. In this study, we used a data-driven multivariate approach to explore the impaired communication between distributed neuronal networks in 10 patients with Parkinson's disease and freezing of gait, and 10 matched patients with no clinical history of freezing behaviour. Patients performed a virtual reality gait task on two separate occasions (once ON and once OFF their regular dopaminergic medication) while functional magnetic resonance imaging data were collected. Group-level independent component analysis was used to extract the subject-specific time courses associated with five well-known neuronal networks: the motor network, the right- and left cognitive control networks, the ventral attention network and the basal ganglia network. We subsequently analysed both the activation and connectivity of these neuronal networks between the two groups with respect to dopaminergic state and cognitive load while performing the virtual reality gait task. During task performance, all patients used the left cognitive control network and the ventral attention network and in addition, showed increased connectivity between the bilateral cognitive control networks. However, patients with freezing demonstrated functional decoupling between the basal ganglia network and the cognitive control network in each hemisphere. This decoupling was also associated with paroxysmal motor arrests. These results support the hypothesis that freezing behaviour in Parkinson's disease is because of impaired communication between complimentary yet competing neural networks.
Publisher: Elsevier BV
Date: 10-2016
Abstract: Protecting the skin from ultraviolet (UV) radiation is critical during adolescence to reduce the risk of developing skin cancer later in life, but adolescents tend to be less likely to engage in sun-protective behaviours than adults. The present study examined changes and trends (2001/02-2011/12) in sun-protection behaviours among adolescents living in Western Australia - a region with high levels of UV radiation. A cross-sectional survey was conducted during 10 summers between 2001/02 and 2011/12 to investigate how often adolescents engaged in various sun-protection behaviours, including outdoor protective measures (wearing a hat, wearing protective clothing, using sunscreen, wearing sunglasses, seeking shade) and avoidance of UV radiation by staying inside. Hat use significantly decreased between 2001/02 and 2011/12, whereas use of sunscreen and wearing covering clothes were unchanged in most survey years relative to 2001/02. Use of sunglasses peaked in 2006/07 and 2007/08, but returned to first survey year levels in 2011/12, while staying inside was more frequently reported from 2006/07 onwards. New approaches are needed to minimise reactance responses in adolescents while fostering favourable attitudes to sun protection. Implications and opportunities for interventions to promote better sun-protection practices among adolescents are provided.
Publisher: Cambridge University Press (CUP)
Date: 05-05-2022
Publisher: Wiley
Date: 26-06-2019
DOI: 10.1002/MDS.27780
Abstract: Although motor abnormalities have been flagged as potentially the most sensitive and specific clinical features for predicting the future progression to Parkinson's disease, little work has been done to characterize gait and balance impairments in idiopathic rapid eye movement sleep behavior disorder (iRBD). The objective of this study was to quantitatively determine any static balance as well as gait impairments across the 5 independent domains of gait in polysomnography-confirmed iRBD patients using normal, fast-paced, and dual-task walking conditions. A total of 38 participants (24 iRBD, 14 healthy controls) completed the following 5 different walking trials across a pressure sensor carpet: (1) normal pace, (2) fast pace, (3) while counting backward from 100 by 1s, (4) while naming as many animals as possible, (5) while subtracting 7s from 100. Although no gait differences were found between the groups during normal walking, there were significant differences between groups under the fast-paced and dual-task gait conditions. Specifically, in response to the dual tasking, healthy controls widened their step width without changing step width variability, whereas iRBD patients did not widen their step width but, rather, significantly increased their step width variability. Similarly, changes between the groups were observed during fast-paced walking wherein the iRBD patients demonstrated greater step length asymmetry when compared with controls. This study demonstrates that iRBD patients have subtle gait impairments, which likely reflect early progressive degeneration in brainstem regions that regulate both REM sleep and gait coordination. Such gait assessments may be useful as a diagnostic preclinical screening tool for future fulminant gait abnormalities for trials of disease-preventive agents. © 2019 International Parkinson and Movement Disorder Society.
Publisher: Informa UK Limited
Date: 14-12-2022
DOI: 10.1080/14737175.2021.1851198
Abstract: Hallucinations in Parkinson's disease are common, can complicate medication management and significantly impact upon the quality of life of patients and their carers. This review aims to examine current evidence for the management of hallucinations in Parkinson's disease. Treatment of hallucinations in Parkinson's disease should be both in idualized and multifaceted. Screening, education, medication review and the avoidance of common triggers are important. For well-formed visual hallucinations, acetylcholinesterase inhibitors are recommended first-line. Refractory or severe symptoms may require the cautious use of atypical antipsychotics. Antidepressants may be beneficial in the appropriate setting. Unfortunately, current therapies for hallucinations offer only limited benefits and future research efforts are desperately required to improve the management of these challenging symptoms.
Publisher: Oxford University Press (OUP)
Date: 20-05-2022
Abstract: Isolated REM sleep behaviour disorder (iRBD) is a synucleinopathy characterized by abnormal behaviours and vocalizations during REM sleep. Most iRBD patients develop dementia with Lewy bodies, Parkinson's disease or multiple system atrophy over time. Patients with iRBD exhibit brain atrophy patterns that are reminiscent of those observed in overt synucleinopathies. However, the mechanisms linking brain atrophy to the underlying alpha-synuclein pathophysiology are poorly understood. Our objective was to investigate how the prion-like and regional vulnerability hypotheses of alpha-synuclein might explain brain atrophy in iRBD. Using a multicentric cohort of 182 polysomnography-confirmed iRBD patients who underwent T1-weighted MRI, we performed vertex-based cortical surface and deformation-based morphometry analyses to quantify brain atrophy in patients (67.8 years, 84% male) and 261 healthy controls (66.2 years, 75%) and investigated the morphological correlates of motor and cognitive functioning in iRBD. Next, we applied the agent-based Susceptible-Infected-Removed model (i.e. a computational model that simulates in silico the spread of pathologic alpha-synuclein based on structural connectivity and gene expression) and tested if it recreated atrophy in iRBD by statistically comparing simulated regional brain atrophy to the atrophy observed in patients. The impact of SNCA and GBA gene expression and brain connectivity was then evaluated by comparing the model fit to the one obtained in null models where either gene expression or connectivity was randomized. The results showed that iRBD patients present with cortical thinning and tissue deformation, which correlated with motor and cognitive functioning. Next, we found that the computational model recreated cortical thinning (r = 0.51, P = 0.0007) and tissue deformation (r = 0.52, P = 0.0005) in patients, and that the connectome's architecture along with SNCA and GBA gene expression contributed to shaping atrophy in iRBD. We further demonstrated that the full agent-based model performed better than network measures or gene expression alone in recreating the atrophy pattern in iRBD. In summary, atrophy in iRBD is extensive, correlates with motor and cognitive function and can be recreated using the dynamics of agent-based modelling, structural connectivity and gene expression. These findings support the concepts that both prion-like spread and regional susceptibility account for the atrophy observed in prodromal synucleinopathies. Therefore, the agent-based Susceptible-Infected-Removed model may be a useful tool for testing hypotheses underlying neurodegenerative diseases and new therapies aimed at slowing or stopping the spread of alpha-synuclein pathology.
Publisher: Wiley
Date: 28-09-2021
DOI: 10.1002/MDS.28796
Publisher: Wiley
Date: 11-06-2020
DOI: 10.1002/MDS.28114
Publisher: Springer Science and Business Media LLC
Date: 11-2019
DOI: 10.1186/S12909-019-1832-3
Abstract: Recent trends in faculty development demonstrate a shift from short term to long-term programs formal to informal learning in the workplace in idual to group settings and from in idual support to institutional support. The purpose of this study was to develop and evaluate a one-year Clinical Teaching Fellowship (CTF) program designed to equip early career medical practitioners and basic scientists with necessary skills to facilitate Team-based learning (TBL). The CTF program provided formal training, a choice of informal professional development activities, and practical co-teaching opportunities in TBL. Of the 40 registrants, 31 (78%) completed the program. Data were collected via questionnaire and focus group. Data were analysed using descriptive statistics and framework analysis. Participants considered the CTF program as relevant to their needs and useful to their career. Learning was enriched through the combination of training, practical teaching experience alongside senior clinical teachers, the multi-disciplinary context of training and co-teaching in TBLs and the sense of community. Competing clinical responsibilities made it difficult to attend training and TBL teaching. The CTF program provided a longitudinal faculty development framework promoting preparation, practice and development of teaching skills. Securing institutional support to invest in the growth and development of early career teachers is essential to sustained innovation and excellence in teaching.
Publisher: Springer Science and Business Media LLC
Date: 24-10-2020
DOI: 10.1007/S00415-019-09583-8
Abstract: The recent revision of the consensus diagnostic criteria for dementia with Lewy bodies (DLB) incorporates an expansive set of core and supportive clinical features. However, the relationship between all features and optimal methods for their assessment has yet to be assessed within a single cohort. This has the potential to yield novel pathological insights and streamline diagnostic algorithms. Twenty-seven prospectively recruited probable DLB patients and 25 age-matched controls were assessed and core and supportive features scored using a unique combination of established clinical and research instruments. Prevalence of all features was reported and diagnostic methods were evaluated. An exploratory factor analysis was performed to uncover latent associations. Six independent factors were identified accounting for 81% of the diagnostic variance across all core and supportive clinical features. Within these factors, pathologically plausible relationships were highlighted between hallucinations, cognitive fluctuations, and excessive daytime somnolence between REM sleep behaviour disorder (RBD) and postural hypotension as well as between Parkinsonism and urinary disturbance. 'Prodromal' DLB symptoms were represented in the remaining three factors. The UPDRS and RBD screening questionnaire were evaluated for their suitability for detecting DLB core features and a novel DLB-Parkinsonism scale is proposed to help standardize diagnosis (AUC = 0.94 95% CI 0.81-1.00). Clusters of specific core and supportive DLB features are identified, which together with the evaluated screening instruments evaluated, may inform improved strategies to diagnose DLB in clinical and research settings.
Publisher: Springer Science and Business Media LLC
Date: 26-04-2021
DOI: 10.1186/S12909-021-02638-3
Abstract: Two established small-group learning paradigms in medical education include Case-based learning (CBL) and Team-based learning (TBL). Characteristics common to both pedagogies include the use of an authentic clinical case, active small-group learning, activation of existing knowledge and application of newly acquired knowledge. However, there are also variances between the two teaching methods, and a paucity of studies that consider how these approaches fit with curriculum design principles. In this paper we explore student and facilitator perceptions of the two teaching methods within a medical curriculum, using Experience based learning (ExBL) as a conceptual lens. A total of 34/255 (13%) Year 2 medical students completed four CBLs during the 2019 Renal and Urology teaching block, concurrent to their usual curriculum activities, which included weekly TBLs. Questionnaires were distributed to all students ( n = 34) and CBL facilitators ( n = 13). In addition, all students were invited to attend focus groups. Data were analysed using descriptive statistics and thematic analysis. In total, 23/34 (71%) of students and 11/13 (85%) of facilitators completed the questionnaires. Twelve students (35%) participated in focus groups. Findings indicate their experience in CBL to be positive, with many favourable aspects that built on and complemented their TBL experience that provided an emphasis on the basic sciences. The learning environment was enriched by the CBL framework that allowed application of knowledge to solve clinical problems within the small groups with consistent facilitator guidance and feedback, their capacity to focus discussion, and associated efficiencies in learning. While the TBL model was integral in developing students’ knowledge and understanding of basic science concepts, the CBL model was integral in developing students’ clinical reasoning skills. The strengths of CBL relative to TBL included the development of authentic clinical reasoning skills and guided facilitation of small group discussion. Our findings suggest that delivery of a medical curriculum may be enhanced through increased vertical integration, applying TBL in earlier phases of the medical program where the focus is on basic science principles, with CBL becoming more relevant as students move towards clinical immersion.
Publisher: Wiley
Date: 30-12-2018
DOI: 10.1002/MDS.27601
Abstract: Leucine-rich repeat kinase 2 is a potential therapeutic target for the treatment of Parkinson's disease, and clinical trials of leucine-rich repeat kinase 2 inhibitors are in development. The objective of this study was to evaluate phosphorylation of a new leucine-rich repeat kinase 2 substrate, Rab10, for potential use as a target engagement biomarker and/or patient enrichment biomarker for leucine-rich repeat kinase 2 inhibitor clinical trials. Peripheral blood mononuclear cells and neutrophils were isolated from Parkinson's disease patients and matched controls, and treated ex vivo with a leucine-rich repeat kinase 2 inhibitor. Immunoblotting was used to measure levels of leucine-rich repeat kinase 2 and Rab10 and their phosphorylation. Plasma inflammatory cytokines were measured by multiplex enzyme-linked immunosorbent assay. Mononuclear cells and neutrophils of both controls and Parkinson's disease patients responded the same to leucine-rich repeat kinase 2 inhibitor treatment. Leucine-rich repeat kinase 2 levels in mononuclear cells were the same in controls and Parkinson's disease patients, whereas leucine-rich repeat kinase 2 was significantly increased in Parkinson's disease neutrophils. Rab10 T73 phosphorylation levels were similar in controls and Parkinson's disease patients and did not correlate with leucine-rich repeat kinase 2 levels. Immune-cell levels of leucine-rich repeat kinase 2 and Rab10 T73 phosphorylation were associated with plasma inflammatory cytokine levels. Rab10 T73 phosphorylation appears to be a valid target engagement biomarker for potential use in leucine-rich repeat kinase 2 inhibitor clinical trials. However, a lack of association between leucine-rich repeat kinase 2 and Rab10 phosphorylation complicates the potential use of Rab10 phosphorylation as a patient enrichment biomarker. Although replication is required, increased leucine-rich repeat kinase 2 levels in neutrophils from Parkinson's disease patients may have the potential for patient stratification. leucine-rich repeat kinase 2 activity in peripheral immune cells may contribute to an inflammatory phenotype. © 2018 International Parkinson and Movement Disorder Society.
Publisher: Elsevier BV
Date: 2022
Publisher: EDP Sciences
Date: 12-2014
Publisher: Springer Science and Business Media LLC
Date: 2021
Publisher: BMJ
Date: 24-05-2018
DOI: 10.1136/JNNP-2018-ANZAN.24
Abstract: Freezing of gait (FOG) in Parkinson’s disease (PD) is a disabling symptom of advanced PD and is frequently triggered upon passing through narrow spaces such as doorways. 1 Despite being common, the mechanisms underlying this phenomenon are poorly understood. We have previously shown that increased footstep latency in a virtual reality (VR) environment is a surrogate measure of FOG. 2 In this study we aimed to model doorway freezing utilising the VR paradigm in conjunction with functional magnetic resonance imaging (fMRI) to determine the neural correlates of this phenomenon. In our study, nineteen patients who routinely experience FOG performed a previously validated VR gait paradigm 3 where they used foot-pedals to navigate a series of doorways. Patients underwent testing randomised between both their ‘ON’ and ‘OFF’ medication states. Task performance in conjunction with blood oxygenation level dependent signal changes were compared within each patient. We were able to reproduce the finding that patients in the OFF state demonstrated significantly longer ‘footstep’ latencies as they passed through a doorway in the VR environment compared to the ON state. As seen clinically with FOG this locomotive delay was primarily triggered by narrow doorways rather than wide doorways. fMRI analysis revealed that doorway-provoked footstep delay was associated with selective hypoactivation in the pre-supplementary motor area (pSMA) bilaterally. Task-based functional connectivity analyses showed that this delay was inversely correlated with the degree of functional connectivity between the pSMA and the subthalamic nucleus (STN) across both hemispheres. Furthermore, increased frequency of prolonged footstep latency was associated with increased connectivity between the bilateral STN. These findings suggest that the effect of environmental cues on triggering FOG reflects a degree of impaired processing within the pSMA and disrupted signalling between the pSMA and STN, thus implicating the ‘hyperdirect’ pathway in the generation of this phenomenon. . Giladi N, Treves TA, Simon ES, Shabtai H, Orlov Y, Kandinov B, Paleacu D, Korczyn AD. Freezing of gait in patients with advanced Parkinson’s disease. J Neural Transm (Vienna)2001 :53–61. . Matar E, Shine JM, Naismith SL, Lewis SJ.Virtual realitywalking and dopamine: opening new doorways to understanding freezing of gait in Parkinson’s disease. J Neurol Sci 2014 :182–5. . Shine JM, Matar E, Bolitho SJ, Dilda V, Morris TR, Naismith SL, Moore ST, Lewis SJ. Modelling freezing of gait in Parkinson’s disease with a virtual reality paradigm. Gait Posture2013 :104–8.
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.JOCN.2009.12.015
Abstract: Diagnosis of an anaplastic astrocytoma (World Health Organization grade III) is associated with a highly variable prognosis. The identification of clinical markers that allow a more careful delineation of this prognostic spectrum is urgently needed. In this study, we analysed 48 patients with a histological diagnosis of anaplastic astrocytoma and found peritumoral post-gadolinium contrast enhancement to be a clear prognostic marker of poor prognosis. Multivariate analysis also confirmed surgery type, Karnofsky Performance Status score (<70) and increasing age as independent adverse predictors of survival. The survival differences observed in the enhancing and non-enhancing lesions in patients diagnosed with anaplastic astrocytoma supports the existence of a broad anaplastic spectrum of disease, with enhancement being a clinical marker of tumour progression along this spectrum.
Publisher: Springer Science and Business Media LLC
Date: 17-02-2022
DOI: 10.1038/S41531-022-00279-X
Abstract: Cognitive fluctuations are a characteristic and distressing disturbance of attention and consciousness seen in patients with Dementia with Lewy bodies and Parkinson’s disease dementia. It has been proposed that fluctuations result from disruption of key neuromodulatory systems supporting states of attention and wakefulness which are normally characterised by temporally variable and highly integrated functional network architectures. In this study, patients with DLB ( n = 25) and age-matched controls ( n = 49) were assessed using dynamic resting state fMRI. A dynamic network signature of reduced temporal variability and integration was identified in DLB patients compared to controls. Reduced temporal variability correlated significantly with fluctuation-related measures using a sustained attention task. A less integrated (more segregated) functional network architecture was seen in DLB patients compared to the control group, with regions of reduced integration observed across dorsal and ventral attention, sensorimotor, visual, cingulo-opercular and cingulo-parietal networks. Reduced network integration correlated positively with subjective and objective measures of fluctuations. Regions of reduced integration and unstable regional assignments significantly matched areas of expression of specific classes of noradrenergic and cholinergic receptors across the cerebral cortex. Correlating topological measures with maps of neurotransmitter/neuromodulator receptor gene expression, we found that regions of reduced integration and unstable modular assignments correlated significantly with the pattern of expression of subclasses of noradrenergic and cholinergic receptors across the cerebral cortex. Altogether, these findings demonstrate that cognitive fluctuations are associated with an imaging signature of dynamic network impairment linked to specific neurotransmitters/neuromodulators within the ascending arousal system, highlighting novel potential diagnostic and therapeutic approaches for this troubling symptom.
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.JNS.2014.06.054
Abstract: Freezing of gait (FOG) is a disabling form of gait disturbance that is common in the advanced stages of Parkinson's disease (PD). Despite its prevalence, methods of studying and assessing FOG are limited. We have previously shown that a virtual reality paradigm was able to distinguish between those who report FOG ("freezers") and those who do not report FOG ("non-freezers"). In this paradigm, 'freezers' were found to have prolonged footstep latency in response to known triggers of FOG including doorways, sliding doors and dual-tasking. In this study, we employed the same paradigm to assess performance of 27 freezers and 14 non-freezers in their clinical 'on' and 'off' medication states. In this study, only participants in the freezing group demonstrated statistically significant increases in latencies experienced in the 'off' state compared to the 'on' state in response to wide and narrow doorways and the opening of a sliding door. By contrast, these behavioral differences were not apparent in non-freezers. Furthermore the delay was specific to environmental cues and was not due to generalized slowing in the 'off' state. The findings suggest that this motor delay when processing environmentally salient cues is specific to freezers and is partially mediated by dopamine-dependent neurocircuitry.
Publisher: AMPCo
Date: 05-2017
DOI: 10.5694/MJA16.00257
Publisher: Oxford University Press (OUP)
Date: 09-03-2018
DOI: 10.1093/BRAIN/AWY019
Abstract: Freezing of gait is a complex, heterogeneous, and highly variable phenomenon whose pathophysiology and neural signature remains enigmatic. Evidence suggests that freezing is associated with impairments across cognitive, motor and affective domains however, most research to date has focused on investigating one axis of freezing of gait in isolation. This has led to inconsistent findings and a range of different pathophysiological models of freezing of gait, due in large part to the tendency for studies to investigate freezing of gait as a homogeneous entity. To investigate the neural mechanisms of this heterogeneity, we used an established virtual reality paradigm to elicit freezing behaviour in 41 Parkinson's disease patients with freezing of gait and examined in idual differences in the component processes (i.e. cognitive, motor and affective function) that underlie freezing of gait in conjunction with task-based functional MRI. First, we combined three unique components of the freezing phenotype: impaired set-shifting ability, step time variability, and self-reported anxiety and depression in a principal components analysis to estimate the severity of freezing behaviour with a multivariate approach. By combining these measures, we were then able to interrogate the pattern of task-based functional connectivity associated with freezing (compared to normal foot tapping) in a sub-cohort of 20 participants who experienced sufficient amounts of freezing during task functional MRI. Specifically, we used the first principal component from our behavioural analysis to classify patterns of functional connectivity into those that were associated with: (i) increased severity (ii) increased compensation or (iii) those that were independent of freezing severity. Coupling between the cognitive and limbic networks was associated with 'worse freezing severity', whereas anti-coupling between the putamen and the cognitive and limbic networks was related to 'increased compensation'. Additionally, anti-coupling between cognitive cortical regions and the caudate nucleus were 'independent of freezing severity' and thus may represent common neural underpinnings of freezing that are unaffected by heterogenous factors. Finally, we related these connectivity patterns to each of the in idual components (cognitive, motor, affective) in turn, thus exposing latent heterogeneity in the freezing phenotype, while also identifying critical functional network signatures that may represent potential targets for novel therapeutic intervention. In conclusion, our findings provide confirmatory evidence for systems-level impairments in the pathophysiology of freezing of gait and further advance our understanding of the whole-brain deficits that mediate symptom expression in Parkinson's disease.
Publisher: Oxford University Press (OUP)
Date: 12-03-2013
DOI: 10.1093/BRAIN/AWT049
Abstract: Freezing of gait is a devastating symptom of advanced Parkinson's disease yet the neural correlates of this phenomenon remain poorly understood. In this study, severity of freezing of gait was assessed in 18 patients with Parkinson's disease on a series of timed 'up and go' tasks, in which all patients suffered from episodes of clinical freezing of gait. The same patients also underwent functional magnetic resonance imaging with a virtual reality gait paradigm, performance on which has recently been shown to correlate with actual episodes of freezing of gait. Statistical parametric maps were created that compared the blood oxygen level-dependent response associated with paroxysmal motor arrests (freezing) to periods of normal motor output. The results of a random effects analysis revealed that these events were associated with a decreased blood oxygen level-dependent response in sensorimotor regions and an increased response within frontoparietal cortical regions. These signal changes were inversely correlated with the severity of clinical freezing of gait. Motor arrests were also associated with decreased blood oxygen level-dependent signal bilaterally in the head of caudate nucleus, the thalamus and the globus pallidus internus. Utilizing a mixed event-related/block design, we found that the decreased blood oxygen level-dependent response in the globus pallidus and the subthalamic nucleus persisted even after controlling for the effects of cognitive load, a finding which supports the notion that paroxysmal increases in basal ganglia outflow are associated with the freezing phenomenon. This method also revealed a decrease in the blood oxygen level-dependent response within the mesencephalic locomotor region during motor arrests, the magnitude of which was positively correlated with the severity of clinical freezing of gait. These results provide novel insights into the pathophysiology underlying freezing of gait and lend support to models of freezing of gait that implicate dysfunction across coordinated neural networks.
Publisher: Oxford University Press (OUP)
Date: 15-10-2019
DOI: 10.1093/BRAIN/AWZ311
Abstract: Fluctuating cognition is a complex and disabling symptom that is seen most frequently in the context of Lewy body dementias encompassing dementia with Lewy bodies and Parkinson’s disease dementia. In fact, since their description over three decades ago, cognitive fluctuations have remained a core diagnostic feature of dementia with Lewy bodies, the second most common dementia in the elderly. In the absence of reliable biomarkers for Lewy body pathology, the inclusion of such patients in therapeutic trials depends on the accurate identification of such core clinical features. Yet despite their diagnostic relevance, cognitive fluctuations remain poorly understood, in part due to the lack of a cohesive clinical and scientific explanation of the phenomenon itself. Motivated by this challenge, the present review examines the history, clinical phenomenology and assessment of cognitive fluctuations in the Lewy body dementias. Based on these data, the key neuropsychological, neurophysiological and neuroimaging correlates of cognitive fluctuations are described and integrated into a novel testable heuristic framework from which new insights may be gained.
Publisher: Wiley
Date: 13-06-2022
DOI: 10.1002/MDC3.13488
Abstract: Dementia with Lewy bodies (DLB) is a common cause of dementia with poor prognosis and high hospitalization rates. DLB is frequently misdiagnosed, with clinical features that overlap significantly with other diseases including Parkinson's disease (PD). Clinical instruments that discriminate and track the progression of cognitive impairment in DLB are needed. The current study was designed to assess the utility of a mental rotation (MR) task for assessing visuospatial impairments in early DLB. Accuracy of 22 DLB patients, 22 PD patients and 22 age‐matched healthy controls in the MR task were compared at comparing shapes with 0°, 45° and 90° rotations. Healthy controls and PD patients performed at similar levels while the DLB group were significantly impaired. Further, impairment in the visuospatial and executive function measures correlated with MR poor outcomes. These findings support the MR task as an objective measure of visuospatial impairment with the ability to adjust difficulty to suit impairments in a DLB population. This would be a useful tool within clinical trials.
Publisher: Springer Science and Business Media LLC
Date: 11-03-2021
Publisher: Elsevier BV
Date: 07-2023
Publisher: Oxford University Press (OUP)
Date: 18-03-2019
DOI: 10.1093/BRAIN/AWZ034
Abstract: Using a dynamic graph theoretical approach, Shine et al. show that in iduals with Parkinson’s disease demonstrate heightened network-level integration during the ‘Off’ state that is inversely correlated with motor symptom severity. Network-level integration relates to two measures of neurocognitive reserve, suggesting a protective function for ‘Off’ state integration.
Publisher: Public Library of Science (PLoS)
Date: 30-01-2013
Publisher: MDPI AG
Date: 22-11-2022
Abstract: Dementia with Lewy bodies (DLB) is an insidious neurodegenerative disease characterised by a precipitous decline in cognition, sleep disturbances, motor impairment and psychiatric features. Recently, criteria for prodromal DLB (pDLB) including clinical features and biomarkers have been put forward to aid the classification and research of this ambiguous cohort of patients. Researchers can use these criteria to classify patients with mild cognitive impairment (MCI) with Lewy bodies (MCI-LB) as either possible (either one core clinical feature or one biomarker are present) or probable pDLB (at least two core clinical features, or one core clinical feature and at least one biomarker present). However, as isolated REM sleep behaviour disorder (iRBD) confirmed with polysomnography (PSG) can be included as both a clinical and a biomarker feature, potentially reducing the specificity of these diagnostic criteria. To address this issue, the current study classified a cohort of 47 PSG-confirmed iRBD patients as probable prodromal DLB only in the presence of an additional core feature or if there was an additional non-PSG biomarker. Thirteen iRBD patients demonstrated MCI (iRBD-MCI). In the iRBD-MCI group, one presented with parkinsonism and was thus classified as probable pDLB, whilst the remaining 12 were classified as only possible pDLB. All patients performed three tasks designed to measure attentional deficits, visual hallucinations and visuospatial impairment. Patients also attended clinical follow-ups to monitor for transition to DLB or another synucleinopathy. Findings indicated that the only patient categorised by virtue of having two core clinical features as probable pDLB transitioned over 28 months to a diagnosis of DLB. The performance of this probable pDLB patient was also ranked second-highest for their hallucinatory behaviours and had comparatively lower visuospatial accuracy. These findings highlight the need for more stringent diagnostic research criteria for pDLB, given that only one of the 13 patients who would have satisfied the current guidelines for probable pDLB transitioned to DLB after two years and was indeed the patient with two orthogonal core clinical features.
Publisher: AMPCo
Date: 09-2017
DOI: 10.5694/MJA17.00321
Abstract: Rapid eye movement (REM) sleep behaviour disorder (RBD) is a parasomnia characterised by the loss of the normal atonia during the REM stage of sleep, resulting in overt motor behaviours that usually represent the enactment of dreams. Patients will seek medical attention due to sleep-related injuries or unpleasant dream content. Idiopathic RBD which occurs independently of any other disease occurs in up to 2% of the older population. Meanwhile, secondary RBD is very common in association with certain neurodegenerative conditions. RBD can also occur in the context of antidepressant use, obstructive sleep apnoea and narcolepsy. RBD can be diagnosed with a simple screening question followed by confirmation with polysomnography to exclude potential mimics. Treatment for RBD is effective and involves treatment of underlying causes, modification of the sleep environment, and pharmacotherapy with either clonazepam or melatonin. An important finding in the past decade is the recognition that almost all patients with idiopathic RBD will ultimately go on to develop Parkinson disease or dementia with Lewy bodies. This suggests that idiopathic RBD represents a prodromal phase of these conditions. Physicians should be aware of the risk of phenoconversion. They should educate idiopathic RBD patients to recognise the symptoms of these conditions and refer as appropriate for further testing and enrolment into research trials focused on neuroprotective measures.
Publisher: Cold Spring Harbor Laboratory
Date: 02-08-2018
DOI: 10.1101/382994
Abstract: Parkinson’s disease is primarily characterised by diminished dopaminergic function, however the impact of these impairments on large-scale brain dynamics remains unclear. It has been difficult to disentangle the direct effects of Parkinson’s disease from compensatory changes that reconfigure the functional signature of the whole brain network. To examine the causal role of dopamine depletion in network-level topology, we investigated time-varying network structure in 37 in iduals with idiopathic Parkinson’s disease, both ‘On’ and ‘Off’ dopamine replacement therapy, along with 50 age-matched, healthy control subjects using resting-state functional MRI. By tracking dynamic network-level topology, we found that the Parkinson’s disease ‘Off’ state was associated with greater network-level integration than in the ‘On’ state. The extent of integration in the ‘Off’ state inversely correlated with motor symptom severity, suggesting that a shift toward a more integrated network topology may be a compensatory mechanism associated with preserved motor function in the dopamine depleted ‘Off’ state. Furthermore, we were able to demonstrate that measures of both cognitive and brain reserve (i.e., premorbid intelligence and whole brain grey matter volume) had a positive relationship with the relative increase in network integration observed in the dopaminergic ‘Off’ state. This suggests that each of these factors plays an important role in promoting network integration in the dopaminergic ‘Off’ state. Our findings provide a mechanistic basis for understanding the PD ‘Off’ state and provide a further conceptual link with network-level reconfiguration. Together, our results highlight the mechanisms responsible for pathological and compensatory change in Parkinson’s disease.
Publisher: Cold Spring Harbor Laboratory
Date: 06-12-2020
DOI: 10.1101/2020.12.04.412551
Abstract: Previous research has shown that the autonomic nervous system provides essential constraints over ongoing cognitive function. However, there is currently a relative lack of direct empirical evidence for how this interaction manifests in the brain at the macro-scale level. Here, we examine the role of ascending arousal and attentional load on large-scale network dynamics by combining pupillometry, functional MRI and graph theoretical analysis to analyze data from a visual motion-tracking task with a parametric load manipulation. We found that attentional load effects were observable in measures of pupil diameter and in a set of brain regions that parametrically modulated their BOLD activity and meso-scale network-level integration. In addition, the regional patterns of network reconfiguration were correlated with the spatial distribution of the α 2a adrenergic receptor. Our results further solidify the relationship between ascending noradrenergic activity, large-scale network integration, and cognitive task performance. In our daily lives, it is usual to encounter highly demanding cognitive tasks. They have been traditionally regarded as challenges that are solved mainly through cerebral activity, specifically via information-processing steps carried by neurons in the cerebral cortex. Activity in cortical networks thus constitutes a key factor for improving our understanding cognitive processes. However, recent evidence has shown that evolutionary older players in the central nervous system, such as brainstem’s ascending modulatory systems, might play an equally important role in erse cognitive mechanisms. Our article examines the role of the ascending arousal system on large-scale network dynamics by combining pupillometry, functional MRI and graph theoretical analysis .
Publisher: Medknow
Date: 2020
Publisher: Wiley
Date: 10-11-2022
DOI: 10.1002/JNR.25145
Abstract: Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50–70 years is associated with reduced short‐interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre‐supplementary motor area (pre‐SMA). Short‐interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired‐pulse transcranial magnetic stimulation in 23 healthy adults with normal ( n = 14 61 ± 7 yrs) or abnormally enlarged (hyperechogenic n = 9 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN− and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre‐SMA neurochemistry. There was no relationship between area of SN echogenicity and short‐interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex ( p = .005 multivariate regression), evidenced by the litude of the conditioned motor evoked potential (MEP) at the 10–12 ms interstimulus interval. This relationship was not present on the left side. Pre‐SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease.
Publisher: Cold Spring Harbor Laboratory
Date: 02-09-2022
DOI: 10.1101/2022.09.01.22279508
Abstract: Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal synucleinopathy characterized by several changes including brain atrophy. The mechanisms underlying atrophy in iRBD are poorly understood. Here, we performed imaging transcriptomics and comprehensive spatial mapping in a multicentric cohort of 171 polysomnography-confirmed iRBD patients and 238 controls with T1-weighted MRI to investigate the gene expression patterns and the specific neurotransmitter, functional, cytoarchitectonic, and cognitive brain systems associated with cortical thinning in iRBD. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the thinning occurring in iRBD. Moreover, we demonstrated that thinning was constrained by the brain’s connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with thickness, changes in cortical surface area related to distinct gene and spatial mapping patterns. This study demonstrates that the development of atrophy in synucleinopathies is constrained by specific genes and networks.
Publisher: Wiley
Date: 07-12-2020
DOI: 10.1002/ANA.25962
Abstract: Isolated (or idiopathic) rapid eye movement sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Biomarkers are lacking to predict conversion to a dementia or a motor‐first phenotype. Here, we aimed at identifying a brain‐clinical signature that predicts dementia in iRBD. A brain‐clinical signature was identified in 48 patients with polysomnography‐confirmed iRBD using partial least squares between brain deformation and 27 clinical variables. The resulting variable was applied to 78 patients with iRBD followed longitudinally to predict conversion to a synucleinopathy, specifically DLB. The deformation scores from patients with iRBD were compared with 207 patients with PD, DLB, or prodromal DLB to assess if scores were higher in DLB compared to PD. One latent variable explained 31% of the brain‐clinical covariance in iRBD, combining cortical and subcortical deformation and subarachnoid/ventricular expansion to cognitive and motor variables. The deformation score of this signature predicted conversion to a synucleinopathy in iRBD ( p = 0.036, odds ratio [OR] = 2.249 95% confidence interval [CI] = 1.053–4.803), specifically to DLB (OR = 4.754 95% CI = 1.283–17.618, p = 0.020) and not PD ( p = 0.286). Patients with iRBD who developed dementia had scores similar to clinical and prodromal patients with DLB but higher scores compared with patients with PD. The deformation score also predicted cognitive performance over 1, 2, and 4 years in patients with PD. We identified a brain‐clinical signature that predicts conversion in iRBD to more severe/dementing forms of synucleinopathy. This pattern may serve as a new biomarker to optimize patient care, target risk reduction strategies, and administer neuroprotective trials. ANN NEUROL 2021 :341–357
Publisher: SAGE Publications
Date: 31-10-2019
Abstract: Cognitive fluctuations (CFs) are a core diagnostic feature of dementia with Lewy bodies (DLB). Detection of CF is still mostly based on subjective reports from the patient or informant more quantitative measures are likely to improve the accuracy for the diagnosis of DLB. The purpose of the current study is to test whether performance on the Sustained Attention Response Task (SART) could distinguish those patients with DLB with and without CF. Twenty-four patients with DLB were tested on the SART and performance was related to scores on the Clinical Assessment of Fluctuations (CAFs) and One Day Fluctuation Assessment Scale (ODFAS). The number of “misses” made was a significant predictor of their fluctuation severity, attentional performance, disorganized thinking, and language production ratings on the ODFAS. However, measures on the SART did not correlate with measures on the CAF scale. In conclusion, these findings suggest that SART is a feasible measure of sustained attention in this population and has clinical and diagnostic relevance to the measurement of CF, particularly those aspects measured by the ODFAS.
Publisher: Wiley
Date: 11-11-2019
DOI: 10.1111/JSR.12939
Abstract: The vast majority of patients with idiopathic rapid eye movement sleep behaviour disorder will develop a neurodegenerative α‐synuclein‐related condition, such as Parkinson’s disease or dementia with Lewy bodies. The pathology underlying dream enactment overlaps anatomically with the brainstem regions that regulate circadian core body temperature. Previously, nocturnal core body temperature regulation has been shown to be impaired in Parkinson’s disease. However, no study to date has investigated nocturnal core body temperature changes in patients with idiopathic rapid eye movement sleep behaviour disorder, which may prove to be an early objective biomarker for α‐synucleinopathies. Ten healthy controls, 15 patients with idiopathic rapid eye movement sleep behaviour disorder, 31 patients with Parkinson’s disease and six patients with dementia with Lewy bodies underwent clinical assessment and nocturnal polysomnography with core body temperature monitoring. A validated cosinor method was utilised for core body temperature analysis. No differences in mesor, nadir or time of nadir were observed between groups. However, when compared with healthy controls, the litude of the nocturnal core body temperature (mesor minus nadir) was significantly reduced in patients with idiopathic rapid eye movement sleep behaviour disorder, Parkinson’s disease with concurrent rapid eye movement sleep behaviour disorder and dementia with Lewy bodies ( p 0.001, p = 0.043 and p = 0.017, respectively). Importantly, this relationship was not seen in those patients with Parkinson’s disease without rapid eye movement sleep behaviour disorder. In addition, there was a significant negative correlation between litude of the core body temperature and self‐reported rapid eye movement sleep behaviour disorder symptoms. Changes in thermoregulatory circadian rhythm may be specifically associated with the pathology underlying rapid eye movement sleep behaviour disorder rather than simply that of α‐synucleinopathy. These findings implicate thermoregulatory dysfunction as a potential early biomarker for development of rapid eye movement sleep behaviour disorder‐associated neurodegeneration, and suggest that subpopulations with differing pathological underpinnings might exist in Parkinson’s disease.
Publisher: MIT Press - Journals
Date: 2021
DOI: 10.1162/NETN_A_00205
Abstract: Previous research has shown that the autonomic nervous system provides essential constraints over ongoing cognitive function. However, there is currently a relative lack of direct empirical evidence for how this interaction manifests in the brain at the macroscale level. Here, we examine the role of ascending arousal and attentional load on large-scale network dynamics by combining pupillometry, functional MRI, and graph theoretical analysis to analyze data from a visual motion-tracking task with a parametric load manipulation. We found that attentional load effects were observable in measures of pupil diameter and in a set of brain regions that parametrically modulated their BOLD activity and mesoscale network-level integration. In addition, the regional patterns of network reconfiguration were correlated with the spatial distribution of the α2a adrenergic receptor. Our results further solidify the relationship between ascending noradrenergic activity, large-scale network integration, and cognitive task performance.
Publisher: Wiley
Date: 22-08-2021
DOI: 10.1111/TCT.13411
Abstract: The Clinical Teacher Training (CTT) programme was originally developed as an interprofessional, blended learning programme, to support health professionals working across health services within Australia, although it has also been delivered internationally. With the disruption of COVID‐19, we rapidly moved to ‘online only’ delivery. We sought to modify the programme, ensuring that the constructivist paradigms important for our learner experience through the original blended format were maintained in the online platform. Consisting of 10 modules on a range of topics, the new CTT online only programme was facilitated online across 6 weeks with asynchronous and synchronous assessable activities, and provision of peer and facilitator feedback. The learning outcomes for each module were similar to the ‘blended learning’ format. The new programme was delivered three times throughout 2020 and completed by a total of 208 health professionals from across 10 metropolitan and rural health districts. The focus of our evaluation was on the programme's final 2020 iteration, for which we had ethics approval. Participants ( n = 59) were from erse health professions, across five metropolitan and rural health districts. We prioritised the learner experience in constructing our evaluation strategy. Quantitative and qualitative data were collected by post‐course questionnaire and analysed using descriptive statistics and thematic analysis. Twenty participants (34%) responded to the post‐course questionnaire. Participants valued the structure, topics, clear outcomes, timeframe, online resources, small group activities, feedback and the flexibility and accessibility afforded by online only delivery. However, participants identified a need for additional ‘real‐time’ engagement in activities. Faculty were surprised by the time required to adequately facilitate online learning, and similarly, valued the real‐time interactions. The online only CTT programme provided an excellent, scalable framework to ensure continued provision of a relevant and accessible training resource for clinicians working in metropolitan and regional/rural health services. Learner‐reported achievement of programme learning outcomes was not negatively impacted by online only delivery. Balancing these resource advantages with learner preferences and our desire to build active teaching networks, we will continue to host the majority of the programme online, while offering short face‐to‐face sessions within local contexts.
Publisher: BMJ
Date: 24-05-2018
DOI: 10.1136/JNNP-2018-ANZAN.109
Abstract: Although limbic system dysfunction has been thought to underlie visual hallucinations in patients with Lewy body disorders, neuropathology within thalamic structures subserving limbic functions have not been examined. In this study, we assessed the degree of neuronal degeneration in thalamic regions involved in perceptual integration in patients with Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). Post-mortem s les were acquired from twenty-four in iduals with Lewy body disease (5 PD, 9 PDD, 10 DLB) and 10 age-matched controls. The anterior principal (AP) and mediodorsal (MD) thalamic nuclei were delineated and analysed using stereological and quantitative neuropathological techniques. Volume loss within the MD nucleus was observed in patients with DLB (31%) and PDD (18%) but not PD compared to controls (ANOVA, p .05). The atrophy was significantly greater in those patients with hallucinations than those without (p .05). Somal atrophy was seen in all patient groups and did not correlate with volume loss or visual hallucinations. Interestingly, there was no neuronal loss in this region compared to controls in the Lewy body disease groups. Analysis of the AP nucleus revealed similar patterns of volume loss but with somal atrophy only in patients with PDD and DLB. Both these measures did not correlate significantly with visual hallucinations, but was significantly different in patients with dementia compared to PD only and controls (p .05). These results suggest that afferent denervation of the mediodorsal thalamus may contribute to visual hallucinations. This appears to support models that implicate upstream components of the limbic circuitry in the generation of this phenomenon.
Publisher: Public Library of Science (PLoS)
Date: 21-06-2013
Publisher: Wiley
Date: 07-06-2021
Publisher: Frontiers Media SA
Date: 2013
Publisher: SAGE Publications
Date: 29-04-2019
Abstract: There is emerging evidence indicating that color discrimination impairments can predict the development of Lewy body dementia in patients with rapid eye movement sleep behavior disorder, Parkinson disease, and in patients with mild cognitive impairment. Despite this clear relationship, color vision deficits are not seen uniformly in patients with dementia with Lewy bodies (DLB), suggesting a more nuanced association with the underlying neuropathology. Visual hallucinations represent a discriminating feature of DLB, and recent evidence implicates visual pathway dysfunction as a significant contributor to this phenomenon. In this study, we examined the relationship between color vision impairment and visual hallucinations, along with other clinical and neuropsychological features in 24 well-characterized patients with DLB alongside 25 healthy controls. Color discrimination impairment was seen in 16 (67%) of 24 DLB participants with a higher error score relative to controls ( P = .001). We demonstrate for the first time a strong association between color discrimination errors on the Farnsworth-Munsell 100 hue test and both the presence and severity of hallucinatory symptoms in DLB based on clinician-derived ( P = .008) and questionnaire-derived ( P = .03) measures. Correlation with clinical and neuropsychological variables revealed that color discrimination is significantly related to visuospatial difficulties measured by the clock-drawing task ( P = .02) but not to global measures of cognition, motor severity, age, or disease duration in our cohort. Factor analysis confirmed a unique relationship between color discrimination, visual hallucinations, and visuospatial function. Our results suggest that color discrimination does not simply relate to dementia but rather indexes higher order perceptual deficits that may predict visual hallucinations in Lewy body disorders and share a common pathophysiological substrate.
Publisher: American Physical Society (APS)
Date: 04-09-2009
Publisher: Wiley
Date: 13-06-2013
DOI: 10.1002/HBM.22321
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-09-2021
DOI: 10.1212/WNL.0000000000012450
Abstract: This study aimed to quantify the trajectory and magnitude of change of the key clinical features and corresponding symptom domains of dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD), including global cognition, parkinsonism, recurrent visual hallucinations, cognitive fluctuations, and sleep disturbance. One hundred sixteen patients with Lewy body dementia (DLB = 72, PDD = 44) underwent assessment at baseline and 3 and 6 months as part of a prospective multicenter randomized controlled trial. Linear mixed models were constructed for core outcome measures using the Mini-Mental State Examination (MMSE), motor section of the Unified Parkinson's Disease Rating Scale (UPDRS-III), Dementia Cognitive Fluctuations Scale (DCFS), and Neuropsychiatric Inventory (NPI). Within the time frame of our study (6 months), we were able to identify a significant cognitive decline of 1.3 points on the MMSE ( p = 0.002) and significant worsening of motor parkinsonism with an increase in UPDRS-III score of 3.2 points ( p = 0.018). Fluctuation severity also increased using the DCFS with a 6-month change in score of 1.3 points ( p = 0.001). Uniquely, a signal for increased severity of sleep symptoms of 1.2 points (NPI-sleep) was also detectable ( p = 0.04). Significant changes in neuropsychiatric symptoms were not detected. There was no difference in rates of change of scores between DLB and PDD. Clinically significant rates of change in core clinical features can be detected and quantified in Lewy body dementia over a relatively short period (6 months) using common clinical instruments and thus may be useful as clinical endpoints for therapeutic trials of disease-modifying and symptomatic agents.
Publisher: Wiley
Date: 13-01-2019
DOI: 10.1002/HBM.24506
Publisher: Informa UK Limited
Date: 2023
DOI: 10.2147/CIA.S361519
Publisher: Oxford University Press (OUP)
Date: 24-02-2023
Abstract: Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson’s disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49–87) years 83% men] and 238 healthy controls [66.6 ± 7.9 (41–88) years 77% men] with T1-weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain’s structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer’s disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain’s structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer’s disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks.
Publisher: Cold Spring Harbor Laboratory
Date: 28-09-2021
DOI: 10.1101/2021.09.28.462089
Abstract: The rise in herbicide resistance over recent decades threatens global agriculture and food security and so discovery of new modes of action is increasingly important. Here we reveal linezolid, an oxazolidinone antibiotic that inhibits microbial translation, is also herbicidal. To validate the herbicidal mode of action of linezolid we confirmed its micromolar inhibition is specific to chloroplast translation and did not affect photosynthesis directly. To assess the herbicide potential of linezolid, testing against a range of weed and crop species found it effective pre- and post-emergence. Using structure-activity analysis we identified the critical elements for herbicidal activity, but importantly also show, using antimicrobial susceptibility assays, that separation of antibacterial and herbicidal activities was possible. Overall these results validate chloroplast translation as a viable herbicidal target.
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.PARKRELDIS.2013.06.002
Abstract: The freezing phenomenon is among the most disabling symptoms of Parkinson's disease (PD) manifesting most commonly as Freezing of Gait with a paroxysmal cessation of effective stepping. Recent studies have suggested that freezing is related to both impairments in conflict resolution as well as the processing of environmentally salient information. In this study, we utilized a virtual reality gait paradigm to investigate differences in motor outflow between PD patients with (n = 36) and without (n = 37) Freezing of Gait, as well as age-matched healthy controls (n = 18). Subjects were required to navigate a realistic on-screen environment with the use of foot pedals to simulate stepping whilst responding to either cues associated with conflict resolution (congruent 'Red', 'Green' or 'Blue') or environmental salience (wide, narrow and sliding doorways). Footstep latency was used as a measure of motor output. Significantly increased stepping latencies were observed in freezers compared to non-freezers (p = 0.004) and controls (p = 0.016) in response to stimuli requiring the inhibition of implicitly cued behavior ('red' cue). Patients with Freezing of Gait also demonstrated increased motor latency compared to non-freezers and controls specifically in response to environmentally salient triggers including narrow doorways (p = 0.03 and 0.01 respectively) and the opening of a sliding door (p = 0.036 and 0.048 respectively). Performance on the paradigm in relation to these triggers correlated significantly with self-reported freezing severity. These results suggest that deficits in conflict resolution and visuospatial processing may reflect some of the neural mechanisms associated with freezing behavior and that these can be probed in a virtual reality environment.
Location: United Kingdom of Great Britain and Northern Ireland
Location: Australia
Start Date: 2021
End Date: 2019
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2019
End Date: 2019
Funder: Department of Education, Skills and Employment
View Funded ActivityStart Date: 2018
End Date: 2021
Funder: National Health and Medical Research Council
View Funded Activity