17 results found
Young PNE, Estarellas M, Coomans E, et al., 2020, Imaging biomarkers in neurodegeneration: current and future practices, Alzheimer's Research and Therapy, Vol: 12, Pages: 1-17, ISSN: 1758-9193
There is an increasing role for biological markers (biomarkers) in the understanding and diagnosis of neurodegenerative disorders. The application of imaging biomarkers specifically for the in vivo investigation of neurodegenerative disorders has increased substantially over the past decades and continues to provide further benefits both to the diagnosis and understanding of these diseases. This review forms part of a series of articles which stem from the University College London/University of Gothenburg course “Biomarkers in neurodegenerative diseases”. In this review, we focus on neuroimaging, specifically positron emission tomography (PET) and magnetic resonance imaging (MRI), giving an overview of the current established practices clinically and in research as well as new techniques being developed. We will also discuss the use of machine learning (ML) techniques within these fields to provide additional insights to early diagnosis and multimodal analysis.
Suzuki H, Venkataraman AV, Bai W, et al., 2019, Associations of regional brain structural differences with aging, modifiable risk factors for dementia, and cognitive performance, JAMA Network Open, Vol: 2, Pages: 1-19, ISSN: 2574-3805
Importance Identifying brain regions associated with risk factors for dementia could guide mechanistic understanding of risk factors associated with Alzheimer disease (AD).Objectives To characterize volume changes in brain regions associated with aging and modifiable risk factors for dementia (MRFD) and to test whether volume differences in these regions are associated with cognitive performance.Design, Setting, and Participants This cross-sectional study used data from UK Biobank participants who underwent T1-weighted structural brain imaging from August 5, 2014, to October 14, 2016. A voxelwise linear model was applied to test for regional gray matter volume differences associated with aging and MRFD (ie, hypertension, diabetes, obesity, and frequent alcohol use). The potential clinical relevance of these associations was explored by comparing their neuroanatomical distributions with the regional brain atrophy found with AD. Mediation models for risk factors, brain volume differences, and cognitive measures were tested. The primary hypothesis was that common, overlapping regions would be found. Primary analysis was conducted on April 1, 2018.Main Outcomes and Measures Gray matter regions that showed relative atrophy associated with AD, aging, and greater numbers of MRFD.Results Among 8312 participants (mean [SD] age, 62.4 [7.4] years; 3959 [47.1%] men), aging and 4 major MRFD (ie, hypertension, diabetes, obesity, and frequent alcohol use) had independent negative associations with specific gray matter volumes. These regions overlapped neuroanatomically with those showing lower volumes in participants with AD, including the posterior cingulate cortex, the thalamus, the hippocampus, and the orbitofrontal cortex. Associations between these MRFD and spatial memory were mediated by differences in posterior cingulate cortex volume (β = 0.0014; SE = 0.0006; P = .02).Conclusions and Relevance This cross-sectional study
Venkataraman A, Mansur A, Lewis Y, et al., 2019, Evaluation of mitochondrial and synaptic function in Alzheimer’s disease (AD): a [18F]BCPP-EF, [11C]SA4503 and [11C]UCB-J PET study, Journal of Cerebral Blood Flow and Metabolism, Vol: 39, Pages: 121-122, ISSN: 1559-7016
ObjectivesMitochondrial deficits leading to synaptic dysfunction have been hypothesised in the pathophysiology of neurodegenerative disease, with Aβ/tau impairing mitochondrial function in AD. To date a combined evaluation of human mitochondrial and synaptic function has not been performed directly in vivo. We describe the pilot results of MINDMAPS-AD, a study within the MINDMAPS1 programme aiming to evaluate mitochondrial and synaptic function in the brain of patients with MCI/AD. MINDMAPS-AD uses the novel radioligands [18F]BCPP-EF, [11C]SA4503 and [11C]UCB-J, to compare the regional density of mitochondrial complex I (MC1), the sigma 1 receptor (s1R) and synaptic vesicular protein 2A (SV2A) respectively.MethodsSix participants with a range of AD related pathologies, EMCI (n = 2), LMCI (n = 2), and AD (n = 2), were enrolled into the study. Participants fulfilled NIA-AA criteria and were amyloid-beta +ve confirmed by [18F]Florbetaben PET. All participants underwent three PET scans with [18F]BCPP-EF, [11C]SA4503 and [11C]UCB-J. Arterial blood samples were collected and a metabolite corrected arterial plasma input function was estimated to derive regional volumes of distribution (VT). These data were compared to six age/sex matched cognitively normal (CN) healthy subjects recruited for ongoing studies within the MINDMAPS programme. Regions of interest (ROIs) were defined on individual subject MR images using an anatomical atlas and included: frontal cortex, hippocampus, amygdala, anterior cingulate, posterior cingulate, thalamus, temporal cortex, parietal cortex, caudate, putamen, and occipital lobe. Regional target density was evaluated using the VT, as well as VT corrected for the plasma free fraction of the radioligand (fP; VT/fp), and the regional VT ratio versus the VT in the centrum semiovale, a white matter region expected to have low levels of the targets evaluated (DVR). Comparison of regional target density and
Venkataraman AV, Mansur A, Lewis Y, et al., 2019, P2-366: quantifying mitochondrial and synaptic function in Alzheimer’s disease using [18F]bcpp-ef, [11C]sa4503 and [11C]ucb-j pet imaging, Alzheimer's & Dementia, Vol: 15, Pages: P740-P741, ISSN: 1552-5260
BackgroundMitochondrial deficits leading to synaptic dysfunction have been hypothesised in the pathophysiology of AD with Aβ/tau impairing mitochondrial function. To date a combined evaluation of human mitochondrial and synaptic function has not been performed directly in vivo. We describe the pilot results of MINDMAPS‐AD aiming to evaluate mitochondrial and synaptic function in the brain of patients with MCI/AD. The novel radioligands [18F]BCPP‐EF, [11C]SA4503 and [11C]UCB‐J are used to compare the regional density of mitochondrial complex I (MC1), the sigma 1 receptor (s1R) and synaptic vesicular protein 2A (SV2A) respectively.MethodsSix participants with AD related pathologies, EMCI (n=2), LMCI (n=2), and AD (n=2) and six cognitively normal (CN) subjects were enrolled. Participants fulfilled NIA‐AA criteria and were Aβ +ve confirmed by [18F]Florbetaben PET. Participants underwent PET scans with [18F]BCPP‐EF, [11C]SA4503 and [11C]UCB‐J. Regions of interest (ROIs) were defined on subject MR images using an anatomical atlas. Target density was evaluated using the VT, as well as VT corrected for the plasma free fraction (fP; VT/fp), and the regional VT ratio versus the VT in the centrum semiovale, expected to have low levels of the targets (DVR). Comparison of regional target density and fP between AD and CN was performed using a two‐tailed, unpaired student's t‐test.ResultsThe fP values in the AD participants were higher for [18F]BCPP‐EF and [11C]UCB‐J (27%, p < 0.02; and 14%, p < 0.08 respectively) and hence VT/fP and DVR were chosen as the parameters of interest. VT/fP and DVR analyses provided consistent results, with lower mean density of MC1 (‐10%) and SV2A (‐16%) across the brain regions, and higher density of s1R (+16%) in participants with AD. Although statistical significance was reached in only some of the ROI, the overall pattern was consistent across ROI in this small pilot.ConclusionsDifferences in molecular markers of mitochondrial and
Lingford-Hughes A, Durant C, Paterson L, et al., 2018, Using baclofen to explore GABA-B receptor function in alcohol dependence: insights from pharmacokinetic and pharmacodynamic measures, Frontiers in Psychiatry, Vol: 9, ISSN: 1664-0640
Background: The role of GABA-B neurotransmission in addiction has recently received increased attention, with clinical trials indicating that baclofen, a GABA-B receptor agonist, may reduce alcohol consumption, craving and promote abstinence. However, the optimal dose to treat alcohol dependence is unclear with patients requesting and tolerating much higher doses of baclofen, compared with other clinical uses. We assessed the pharmacokinetics and pharmacodynamics (PK/PD) of baclofen to provide insight into GABA-B sensitivity in this patient group, relative to controls.Methods: Male healthy volunteers (controls, n = 12) and abstinent alcohol dependent individuals (AD, n = 8) received single oral doses of baclofen or placebo in a 3-way crossover design. Controls received placebo/10 mg/60 mg baclofen in a randomized, double-blind design, AD received placebo/60 mg/90 mg baclofen in a single-blind design. PK/PD measures were recorded at baseline and multiple time-points up to 6 h post-dosing, including plasma baclofen, plasma growth hormone (GH), Subjective High Assessment Scale (SHAS) and biphasic alcohol effects scale (BAES). Repeated measures ANOVA analysis explored “change from baseline” dose, time, group, and interaction effects, t-tests compared peak effects.Results: Dose-dependent effects of baclofen on PK and PD measures were observed in both control and AD groups. Whilst there were no significant group differences in any baclofen PK parameters (t1/2, tmax, Cmax, AUC), marked differences in PD effects were clearly evident. In controls, 60 mg baclofen significantly increased total SHAS and BAES scores, and significantly increased plasma GH levels compared with placebo, with peak effects at 60–120 min, in line with its PK profile. In AD, 60 mg baclofen had limited effects on these parameters; SHAS scores, BAES scores and plasma GH levels were significantly blunted compared with controls (significant group*time interactions P = 0.0014, 0.0015 and P
Venkataraman A, Perry R, Malhotra P, 2018, Young Onset Dementia
Tyacke R, Myers J, Venkataraman A, et al., 2018, Evaluation of 11C-BU99008, a positron emission tomography ligand for the Imidazoline2 binding site in human brain, Journal of Nuclear Medicine, Vol: 59, Pages: 1597-1602, ISSN: 1535-5667
The imidazoline2 binding sites (I2BS), are thought to be expressed in glia, and implicated in the regulation of glial fibrillary acidic protein. A positron emission tomography (PET) ligand for this target would be important for the investigation of neurodegenerative and neuroinflammatory diseases. 11C BU99008 has previously been identified as a putative PET radioligand. Here we present the first in vivo characterisation of this PET radioligand in humans and assess its test-retest reproducibility. Methods: 14 healthy male volunteers underwent dynamic PET imaging with 11C BU99008 and arterial sampling. Six subjects were used to assess test-retest and eight were used in the pharmacological evaluation, undergoing a second, or third heterologous competition scan with the mixed I2BS/α2 adrenoceptor drug, idazoxan (n=8; 20, 40, 60 and 80 mg) and the mixed irreversible monoamine oxidase (MAO) A/B inhibitor, isocarboxazid (n=4; 50 mg), respectively. Regional time-activity data were generated from arterial plasma input functions corrected for metabolites using the most appropriate model to derive the outcome measure VT (regional total distribution volume). All image processing and kinetic analysis was performed in MIAKAT™ (www.miakat.org). Results: Brain uptake of 11C BU99008 was good with reversible kinetics and a heterogeneous distribution consistent with known I2BS expression. Model selection criteria indicated that the 2-tissue-compartment was preferred. VT estimates were high in the striatum (105±21 mL cm 3), medium in cingulate cortex (62±10 mL cm 3) and low in the cerebellum (41±7 mL cm 3). Test-retest reliability was found to be reasonable. The uptake was dose-dependently reduced by pre-treatment with idazoxan throughout the brain, with an average block across all regions of ~60% (VT≅30 mL cm 3) at the highest dose (80 mg). The median effective dose (ED50) for idazoxan was calculated as 28 mg. Uptake was not blocked by pre-treatme
Venkataraman A, Keat N, Myers J, et al., 2018, First evaluation of PET-based human biodistribution and radiation dosimetry of 11C-BU99008, a tracer for imaging the imidazoline2 binding site, EJNMMI Research, Vol: 8, ISSN: 2191-219X
BackgroundWe measured whole body distribution of 11C-BU99008, a new PET biomarker for non-invasive identification of the imidazoline2 binding site. The purpose of this phase I study was to evaluate the biodistribution and radiation dosimetry of 11C-BU99008 in healthy human subjects.MethodsA single bolus injection of 11C-BU99008 (296 ± 10.5 MBq) was administered to four healthy subjects who underwent whole-body PET/CT over 120 min from the cranial vertex to the mid-thigh. Volumes of interest were drawn around visually identifiable source organs to generate time-activity curves (TAC). Residence times were determined from time-activity curves. Absorbed doses to individual organs and the whole body effective dose were calculated using OLINDA/EXM 1.1 for each subject.ResultsThe highest measured activity concentration was in the kidney and spleen. The longest residence time was in the muscle at 0.100 ± 0.023 h, followed by the liver at 0.067 ± 0.015 h and lungs at 0.052 ± 0.010 h. The highest mean organ absorbed dose was within the heart wall (0.028 ± 0.002 mGy/MBq), followed by the kidneys (0.026 ± 0.005 mGy/MBq). The critical organ was the heart wall. The total mean effective dose averaged over subjects was estimated to be 0.0056 ± 0.0004 mSv/MBq for an injection of 11C-BU99008.ConclusionsThe biodistribution of 11C-BU99008 has been shown here for the first time in humans. Our dosimetry data showed the total mean effective dose over all subjects was 0.0056 ± 0.0004 mSv/MBq, which would result in a total effective dose of 1.96 mSv for a typical injection of 350 MBq of 11C-BU99008. The effective dose is not appreciably different from those obtained with other 11C tracers.
Venkataraman A, Nutt D, 2018, A tale of two moralities: Politicians, doctors, use of addictive substances and lobbying, Drug Science, Policy and Law
Fan Z, Calsolaro V, Mayers J, et al., 2018, Relationship between astrocyte activation using [11C]BU99008 PET, glucose metabolism and amyloid in Alzheimer’s disease: a Dementia Platform UK experimental medicine study, Alzheimer's and Dementia, Vol: 14, Pages: P1640-P1640, ISSN: 1552-5260
Calsolaro V, Mayers J, Fan Z, et al., 2018, Evaluation of novel astrocyte marker [11C]BU99008 PET in Alzheimer’s disease: a Dementia Platform U.K. experimental medicine study, Alzheimer's and Dementia, Vol: 14, Pages: P842-P843, ISSN: 1552-5260
Turton S, Myers J, Mick I, et al., 2018, Blunted endogenous opioid release following an oral dexamphetamine challenge in abstinent alcohol dependent individuals, Molecular Psychiatry, ISSN: 1359-4184
Addiction has been proposed as a ‘reward deficient’ state, which is compensated for with substance use. There is growing evidence of dysregulation in the opioid system, which plays a key role in reward, underpinning addiction. Low levels of endogenous opioids are implicated in vulnerability for developing alcohol dependence (AD) and high mu-opioid receptor (MOR) availability in early abstinence is associated with greater craving. This high MOR availability is proposed to be the target of opioid antagonist medication to prevent relapse. However, changes in endogenous opioid tone in AD are poorly characterised and are important to understand as opioid antagonists do not help everyone with AD. We used [11C]carfentanil, a selective MOR agonist positron emission tomography (PET) radioligand, to investigate endogenous opioid tone in AD for the first time. We recruited 13 abstinent male AD and 15 control participants who underwent two [11C]carfentanil PET scans, one before and one 3 h following a 0.5 mg/kg oral dose of dexamphetamine to measure baseline MOR availability and endogenous opioid release. We found significantly blunted dexamphetamine-induced opioid release in 5 out of 10 regions-of-interest including insula, frontal lobe and putamen in AD compared with controls, but no significantly higher MOR availability AD participants compared with HC in any region. This study is comparable to our previous results of blunted dexamphetamine-induced opioid release in gambling disorder, suggesting that this dysregulation in opioid tone is common to both behavioural and substance addictions.
Edison P, Mayers J, Calsolaro V, et al., 2017, Dementia Platform U.K. Experimental medicine: human in vivo astroglial activation in early Alzheimer’s disease, Alzheimer's and Dementia, Vol: 13, Pages: P1073-P1074, ISSN: 1552-5260
Venkataraman A, Kalk N, Sewell G, et al., 2016, Alcohol and Alzheimer's Disease-Does Alcohol Dependence Contribute to Beta-Amyloid Deposition, Neuroinflammation and Neurodegeneration in Alzheimer's Disease?, Alcohol and Alcoholism, Vol: 52, Pages: 151-158, ISSN: 1464-3502
Aims:To investigate the underlying neurobiology between alcohol use, misuse and dependence and cognitive impairment, particularly Alzheimer's disease (AD).Methods:Review of the literature using searches of Medline, Pubmed, EMBASE, PsycInfo, and meeting abstracts and presentations.Results:The role of alcohol as a risk factor and contributor for cognitive decline associated with AD has received little attention. This is despite the high prevalence of alcohol use, the potential reversibility of a degree of cognitive impairment and the global burden of AD. Until now the focus has largely been on the toxic effects of alcohol, neuronal loss and the role of thiamine.Conclusion:We propose alcohol adds to the cognitive burden seen in dementia through additional mechanisms to neurodegenerative processes or may contribute at various mechanistic points in the genesis and sustenance of AD pathology via neuroinflammation. We describe the common underlying neurobiology in alcohol and AD, and examine ways alcohol likely contributes to neuroinflammation directly via stimulation of Toll-like receptors and indirectly from small bowel changes, hepatic changes, withdrawal and traumatic brain injury to the pathogenesis of AD.
MacLaren T, Townell J, Shanmugham S, et al., 2016, Knowledge of patients' voting rights amongst mental health professionals working in the London Borough of Westminster during the 2015 UK general election, EUROPEAN PSYCHIATRY, Vol: 33, Pages: S450-S450, ISSN: 0924-9338
Townell J, MacLaren T, de Ridder L, et al., 2016, Knowledge and Uptake of Voting Rights By Psychiatric Inpatients in Westminster, London During the 2015 Uk General Election, European Psychiatry, Vol: 33, Pages: S454-S454, ISSN: 0924-9338
<jats:sec id="S0924933800233695_abst0001" sec-type="intro"><jats:title>Introduction</jats:title><jats:p>Being able to vote empowers people with mental illness to have a political voice and promotes social inclusion. Evidence shows that patients with mental illness are less likely to vote compared to the general population.</jats:p></jats:sec><jats:sec id="S0924933800233695_abst0002" sec-type="other"><jats:title>Objective</jats:title><jats:p>This study explores the knowledge and uptake of the voting rights of adult patients in a psychiatric hospital in the 2015 UK general election.</jats:p></jats:sec><jats:sec id="S0924933800233695_abst0003" sec-type="other"><jats:title>Aims</jats:title><jats:p>To understand patients’ eligibility and intentions to vote during the 2015 UK general election. To establish what assistance patients may require in order to vote.</jats:p></jats:sec><jats:sec id="S0924933800233695_abst0004" sec-type="methods"><jats:title>Methods</jats:title><jats:p>A staff-assisted survey was undertaken in all mental health wards in the Gordon Hospital, Westminster prior to the general election in May 2015.</jats:p></jats:sec><jats:sec id="S0924933800233695_abst0005" sec-type="results"><jats:title>Results</jats:title><jats:p>A total of 51 surveys were returned. Seventy-five percent thought they were eligible to vote, and 47% had already registered. Of those that had not yet registered, 37% wanted staff support to do so. Fifty-seven percent of the respondents intended to vote and of those 9 out of 10 intended to vote in person. Twenty-six percent of those intending to vote identified needing assistance in this process.</jats:p></jats:sec><jats:sec id="S0924933800233695_ab
Townell J, MacLaren T, Argent V, et al., 2016, Knowledge and Uptake of Voting Rights By Adults With Mental Illness Living in Supported Accommodation in Westminster (London) During the 2015 Uk General Election, European Psychiatry, Vol: 33, Pages: S453-S454, ISSN: 0924-9338
<jats:sec id="S0924933800233683_abst0001" sec-type="intro"><jats:title>Introduction</jats:title><jats:p>Voting is an essential human right. Being able to vote and participate in elections is an important component of social inclusion; empowering people with mental illness to have a political voice and in turn reducing stigma. Previous research indicates that patients with mental illness are less likely to vote compared to the general population.</jats:p></jats:sec><jats:sec id="S0924933800233683_abst0002" sec-type="other"><jats:title>Objective</jats:title><jats:p>This study explores knowledge and uptake of the voting rights of adults living in mental health supported accommodation in Westminster (London) in the 2015 UK general election.</jats:p></jats:sec><jats:sec id="S0924933800233683_abst0003" sec-type="other"><jats:title>Aims</jats:title><jats:p>Understand patients’ awareness of their eligibility to register and cast their vote. Identify patients’ interest in engaging in the voting process and strategies to overcome potential obstacles.</jats:p></jats:sec><jats:sec id="S0924933800233683_abst0004" sec-type="methods"><jats:title>Methods</jats:title><jats:p>A staff-assisted survey was undertaken in all mental health supported accommodation across Westminster prior to the general election in May 2015.</jats:p></jats:sec><jats:sec id="S0924933800233683_abst0005" sec-type="results"><jats:title>Results</jats:title><jats:p>A total of 142 surveys were returned. Nine out of 10 surveyed believed they were eligible to vote; over half wanted to exercise their right to vote & if registered, a third felt they required assistance to vote.</jats:p></jats:sec><jats:sec id="S092
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.