Publications by authors named "Nicola Filippini"

81 Publications

Functional Connectivity between Task-Positive Networks and the Left Precuneus as a Biomarker of Response to Lamotrigine in Bipolar Depression: A Pilot Study.

Pharmaceuticals (Basel) 2021 Jun 3;14(6). Epub 2021 Jun 3.

Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK.

Treatment of bipolar depression poses a significant clinical challenge. Lamotrigine is one of a few efficacious drugs, however, it needs to be titrated very slowly and response can only be assessed after 10-12 weeks. With only a proportion of patients responding, an exploration of factors underlying treatment responsivity is of paramount clinical importance, as it may lead to an allocation of the drug to those most likely to respond to it. This study aimed at identifying differences in patterns of pre-treatment resting state functional connectivity (rsFC) that may underlie response to lamotrigine in bipolar depression. After a baseline MRI scan, twenty-one patients with bipolar depression were treated with lamotrigine in an open-label design; response, defined as ≥50% decrease in Hamilton Depression Rating Scale (HAMD) score, was assessed after 10-12 weeks of treatment. Twenty healthy controls had a baseline clinical assessment and scan but did not receive any treatment. Fifteen out of 21 (71%) patients responded to lamotrigine. Treatment responsivity was associated with enhanced pre-treatment rsFC of the right fronto-parietal network (FPN) and dorsal attention network (DAN) with left precuneus. The lack of treatment response was additionally characterised by reduced rsFC: of the DAN with right middle temporal gyrus; of the default mode network (DMN) with left precuneus; of the extended sensory-motor area with areas including the left hippocampus/left amygdala and left subcallosal cortex/nucleus accumbens; and of the left FPN with left inferior temporal gyrus/occipital fusiform gyrus/lateral occipital cortex. The results suggest that preserved rsFC between the FPN and DAN, the networks involved in cognitive control, and the hub of the posterior DMN, the left precuneus, may be critical for good response to lamotrigine as an add-on treatment in patients with bipolar depression. The study also suggests a more general decrease in rsFC to be related to poor treatment responsivity.
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http://dx.doi.org/10.3390/ph14060534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229811PMC
June 2021

Integrating large-scale neuroimaging research datasets: Harmonisation of white matter hyperintensity measurements across Whitehall and UK Biobank datasets.

Neuroimage 2021 08 20;237:118189. Epub 2021 May 20.

Wellcome Centre for Integrative Neuroimaging, Oxford Centre for Functional MRI of the Brain, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Wellcome Centre for Integrative Neuroimaging, Oxford Centre for Human Brain Activity, Department of Psychiatry, University of Oxford, Oxford, UK. Electronic address:

Large scale neuroimaging datasets present the possibility of providing normative distributions for a wide variety of neuroimaging markers, which would vastly improve the clinical utility of these measures. However, a major challenge is our current poor ability to integrate measures across different large-scale datasets, due to inconsistencies in imaging and non-imaging measures across the different protocols and populations. Here we explore the harmonisation of white matter hyperintensity (WMH) measures across two major studies of healthy elderly populations, the Whitehall II imaging sub-study and the UK Biobank. We identify pre-processing strategies that maximise the consistency across datasets and utilise multivariate regression to characterise study sample differences contributing to differences in WMH variations across studies. We also present a parser to harmonise WMH-relevant non-imaging variables across the two datasets. We show that we can provide highly calibrated WMH measures from these datasets with: (1) the inclusion of a number of specific standardised processing steps; and (2) appropriate modelling of sample differences through the alignment of demographic, cognitive and physiological variables. These results open up a wide range of applications for the study of WMHs and other neuroimaging markers across extensive databases of clinical data.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285593PMC
August 2021

White matter hyperintensities classified according to intensity and spatial location reveal specific associations with cognitive performance.

Neuroimage Clin 2021 7;30:102616. Epub 2021 Mar 7.

Wellcome Centre for Integrative Neuroimaging, Oxford Centre for Functional MRI of the Brain, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Wellcome Centre for Integrative Neuroimaging, Oxford Centre for Human Brain Activity, Department of Psychiatry, University of Oxford, Oxford, UK.

White matter hyperintensities (WMHs) on T-weighted images are radiological signs of cerebral small vessel disease. As their total volume is variably associated with cognition, a new approach that integrates multiple radiological criteria is warranted. Location may matter, as periventricular WMHs have been shown to be associated with cognitive impairments. WMHs that appear as hypointense in T-weighted images (Tw) may also indicate the most severe component of WMHs. We developed an automatic method that sub-classifies WMHs into four categories (periventricular/deep and Tw-hypointense/nonTw-hypointense) using MRI data from 684 community-dwelling older adults from the Whitehall II study. To test if location and intensity information can impact cognition, we derived two general linear models using either overall or subdivided volumes. Results showed that periventricular Tw-hypointense WMHs were significantly associated with poorer performance in the trail making A (p = 0.011), digit symbol (p = 0.028) and digit coding (p = 0.009) tests. We found no association between total WMH volume and cognition. These findings suggest that sub-classifying WMHs according to both location and intensity in Tw reveals specific associations with cognitive performance.
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http://dx.doi.org/10.1016/j.nicl.2021.102616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995650PMC
March 2021

Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge.

EClinicalMedicine 2021 Jan 7;31:100683. Epub 2021 Jan 7.

Nuffield Department of Medicine, NIHR Oxford BRC, University of Oxford, Oxford, United Kingdom.

Background: The medium-term effects of Coronavirus disease (COVID-19) on organ health, exercise capacity, cognition, quality of life and mental health are poorly understood.

Methods: Fifty-eight COVID-19 patients post-hospital discharge and 30 age, sex, body mass index comorbidity-matched controls were enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments.

Findings: At 2-3 months from disease-onset, 64% of patients experienced breathlessness and 55% reported fatigue. On MRI, abnormalities were seen in lungs (60%), heart (26%), liver (10%) and kidneys (29%). Patients exhibited changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domains. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance were significantly reduced. The extent of extra-pulmonary MRI abnormalities and exercise intolerance correlated with serum markers of inflammation and acute illness severity. Patients had a higher burden of self-reported symptoms of depression and experienced significant impairment in all domains of quality of life compared to controls (<0.0001 to 0.044).

Interpretation: A significant proportion of patients discharged from hospital reported symptoms of breathlessness, fatigue, depression and had limited exercise capacity. Persistent lung and extra-pulmonary organ MRI findings are common in patients and linked to inflammation and severity of acute illness.

Funding: NIHR Oxford and Oxford Health Biomedical Research Centres, British Heart Foundation Centre for Research Excellence, UKRI, Wellcome Trust, British Heart Foundation.
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http://dx.doi.org/10.1016/j.eclinm.2020.100683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808914PMC
January 2021

Associations between arterial stiffening and brain structure, perfusion, and cognition in the Whitehall II Imaging Sub-study: A retrospective cohort study.

PLoS Med 2020 12 29;17(12):e1003467. Epub 2020 Dec 29.

Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, United Kingdom.

Background: Aortic stiffness is closely linked with cardiovascular diseases (CVDs), but recent studies suggest that it is also a risk factor for cognitive decline and dementia. However, the brain changes underlying this risk are unclear. We examined whether aortic stiffening during a 4-year follow-up in mid-to-late life was associated with brain structure and cognition in the Whitehall II Imaging Sub-study.

Methods And Findings: The Whitehall II Imaging cohort is a randomly selected subset of the ongoing Whitehall II Study, for which participants have received clinical follow-ups for 30 years, across 12 phases. Aortic pulse wave velocity (PWV) was measured in 2007-2009 (Phase 9) and at a 4-year follow-up in 2012-2013 (Phase 11). Between 2012 and 2016 (Imaging Phase), participants received a multimodal 3T brain magnetic resonance imaging (MRI) scan and cognitive tests. Participants were selected if they had no clinical diagnosis of dementia and no gross brain structural abnormalities. Voxel-based analyses were used to assess grey matter (GM) volume, white matter (WM) microstructure (fractional anisotropy (FA) and diffusivity), white matter lesions (WMLs), and cerebral blood flow (CBF). Cognitive outcomes were performance on verbal memory, semantic fluency, working memory, and executive function tests. Of 542 participants, 444 (81.9%) were men. The mean (SD) age was 63.9 (5.2) years at the baseline Phase 9 examination, 68.0 (5.2) at Phase 11, and 69.8 (5.2) at the Imaging Phase. Voxel-based analysis revealed that faster rates of aortic stiffening in mid-to-late life were associated with poor WM microstructure, viz. lower FA, higher mean, and radial diffusivity (RD) in 23.9%, 11.8%, and 22.2% of WM tracts, respectively, including the corpus callosum, corona radiata, superior longitudinal fasciculus, and corticospinal tracts. Similar voxel-wise associations were also observed with follow-up aortic stiffness. Moreover, lower mean global FA was associated with faster rates of aortic stiffening (B = -5.65, 95% CI -9.75, -1.54, Bonferroni-corrected p < 0.0125) and higher follow-up aortic stiffness (B = -1.12, 95% CI -1.95, -0.29, Bonferroni-corrected p < 0.0125). In a subset of 112 participants who received arterial spin labelling scans, faster aortic stiffening was also related to lower cerebral perfusion in 18.4% of GM, with associations surviving Bonferroni corrections in the frontal (B = -10.85, 95% CI -17.91, -3.79, p < 0.0125) and parietal lobes (B = -12.75, 95% CI -21.58, -3.91, p < 0.0125). No associations with GM volume or WMLs were observed. Further, higher baseline aortic stiffness was associated with poor semantic fluency (B = -0.47, 95% CI -0.76 to -0.18, Bonferroni-corrected p < 0.007) and verbal learning outcomes (B = -0.36, 95% CI -0.60 to -0.12, Bonferroni-corrected p < 0.007). As with all observational studies, it was not possible to infer causal associations. The generalisability of the findings may be limited by the gender imbalance, high educational attainment, survival bias, and lack of ethnic and socioeconomic diversity in this cohort.

Conclusions: Our findings indicate that faster rates of aortic stiffening in mid-to-late life were associated with poor brain WM microstructural integrity and reduced cerebral perfusion, likely due to increased transmission of pulsatile energy to the delicate cerebral microvasculature. Strategies to prevent arterial stiffening prior to this point may be required to offer cognitive benefit in older age.

Trial Registration: ClinicalTrials.gov NCT03335696.
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http://dx.doi.org/10.1371/journal.pmed.1003467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771705PMC
December 2020

Prediction of brain age and cognitive age: Quantifying brain and cognitive maintenance in aging.

Hum Brain Mapp 2021 Apr 14;42(6):1626-1640. Epub 2020 Dec 14.

Department of Psychiatry, University of Oxford, Oxford, UK.

The concept of brain maintenance refers to the preservation of brain integrity in older age, while cognitive reserve refers to the capacity to maintain cognition in the presence of neurodegeneration or aging-related brain changes. While both mechanisms are thought to contribute to individual differences in cognitive function among older adults, there is currently no "gold standard" for measuring these constructs. Using machine-learning methods, we estimated brain and cognitive age based on deviations from normative aging patterns in the Whitehall II MRI substudy cohort (N = 537, age range = 60.34-82.76), and tested the degree of correspondence between these constructs, as well as their associations with premorbid IQ, education, and lifestyle trajectories. In line with established literature highlighting IQ as a proxy for cognitive reserve, higher premorbid IQ was linked to lower cognitive age independent of brain age. No strong evidence was found for associations between brain or cognitive age and lifestyle trajectories from midlife to late life based on latent class growth analyses. However, post hoc analyses revealed a relationship between cumulative lifestyle measures and brain age independent of cognitive age. In conclusion, we present a novel approach to characterizing brain and cognitive maintenance in aging, which may be useful for future studies seeking to identify factors that contribute to brain preservation and cognitive reserve mechanisms in older age.
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http://dx.doi.org/10.1002/hbm.25316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978127PMC
April 2021

Neural effects of a single dose of fluoxetine on resting-state functional connectivity in adolescent depression.

J Psychopharmacol 2020 12 4;34(12):1461-1465. Epub 2020 Nov 4.

Department of Psychiatry, University of Oxford, Oxford, UK.

Fluoxetine is commonly prescribed in adolescent depression, but the neural mechanisms underlying its action remain poorly understood. Here, we used resting-state functional magnetic resonance imaging to investigate the effects of a single dose of fluoxetine vs. placebo in adolescents with major depressive disorder. In contrast with previous studies in adults that have demonstrated an acute effect of antidepressants on activity within the default mode network, a single dose of fluoxetine did not alter activity in this network in adolescent depression. There were unexpected group activity differences in the motor network, which should be clarified in future research.
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http://dx.doi.org/10.1177/0269881120959608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708665PMC
December 2020

Association of midlife stroke risk with structural brain integrity and memory performance at older ages: a longitudinal cohort study.

Brain Commun 2020 7;2(1):fcaa026. Epub 2020 Mar 7.

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK.

Cardiovascular health in midlife is an established risk factor for cognitive function later in life. Knowing mechanisms of this association may allow preventative steps to be taken to preserve brain health and cognitive performance in older age. In this study, we investigated the association of the Framingham stroke-risk score, a validated multifactorial predictor of 10-year risk of stroke, with brain measures and cognitive performance in stroke-free individuals. We used a large ( = 800) longitudinal cohort of community-dwelling adults of the Whitehall II imaging sub-study with no obvious structural brain abnormalities, who had Framingham stroke risk measured five times between 1991 and 2013 and MRI measures of structural integrity, and cognitive function performed between 2012 and 2016 [baseline mean age 47.9 (5.2) years, range 39.7-62.7 years; MRI mean age 69.81 (5.2) years, range 60.3-84.6 years; 80.6% men]. Unadjusted linear associations were assessed between the Framingham stroke-risk score in each wave and voxelwise grey matter density, fractional anisotropy and mean diffusivity at follow-up. These analyses were repeated including socio-demographic confounders as well as stroke risk in previous waves to examine the effect of residual risk acquired between waves. Finally, we used structural equation modelling to assess whether stroke risk negatively affects cognitive performance via specific brain measures. Higher unadjusted stroke risk measured at each of the five waves over 20 years prior to the MRI scan was associated with lower voxelwise grey and white matter measures. After adjusting for socio-demographic variables, higher stroke risk from 1991 to 2009 was associated with lower grey matter volume in the medial temporal lobe. Higher stroke risk from 1997 to 2013 was associated with lower fractional anisotropy along the corpus callosum. In addition, higher stroke risk from 2012 to 2013, sequentially adjusted for risk measured in 1991-94, 1997-98 and 2002-04 (i.e. 'residual risks' acquired from the time of these examinations onwards), was associated with widespread lower fractional anisotropy, and lower grey matter volume in sub-neocortical structures. Structural equation modelling suggested that such reductions in brain integrity were associated with cognitive impairment. These findings highlight the importance of considering cerebrovascular health in midlife as important for brain integrity and cognitive function later in life (ClinicalTrials.gov Identifier: NCT03335696).
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http://dx.doi.org/10.1093/braincomms/fcaa026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491431PMC
March 2020

Association of trajectories of depressive symptoms with vascular risk, cognitive function and adverse brain outcomes: The Whitehall II MRI sub-study.

J Psychiatr Res 2020 12 9;131:85-93. Epub 2020 Sep 9.

Department of Psychiatry, University of Oxford, Oxford, UK. Electronic address:

Background: Trajectories of depressive symptoms over the lifespan vary between people, but it is unclear whether these differences exhibit distinct characteristics in brain structure and function.

Methods: In order to compare indices of white matter microstructure and cognitive characteristics of groups with different trajectories of depressive symptoms, we examined 774 participants of the Whitehall II Imaging Sub-study, who had completed the depressive subscale of the General Health Questionnaire up to nine times over 25 years. Twenty-seven years after the first examination, participants underwent magnetic resonance imaging to characterize white matter hyperintensities (WMH) and microstructure and completed neuropsychological tests to assess cognition. Twenty-nine years after the first examination, participants completed a further cognitive screening test.

Outcomes: Using K-means cluster modelling, we identified five trajectory groups of depressive symptoms: consistently low scorers ("low"; n = 505, 62·5%), a subgroup with an early peak in depression scores ("early"; n = 123, 15·9%), intermediate scorers ("middle"; n = 89, 11·5%), a late symptom subgroup with an increase in symptoms towards the end of the follow-up period ("late"; n = 29, 3·7%), and consistently high scorers ("high"; n = 28, 3·6%). The late, but not the consistently high scorers, showed higher mean diffusivity, larger volumes of WMH and impaired executive function. In addition, the late subgroup had higher Framingham Stroke Risk scores throughout the follow-up period, indicating a higher load of vascular risk factors.

Interpretation: Our findings suggest that tracking depressive symptoms in the community over time may be a useful tool to identify phenotypes that show different etiologies and cognitive and brain outcomes.
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http://dx.doi.org/10.1016/j.jpsychires.2020.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063684PMC
December 2020

Multimodal brain-age prediction and cardiovascular risk: The Whitehall II MRI sub-study.

Neuroimage 2020 11 21;222:117292. Epub 2020 Aug 21.

Department of Psychiatry, University of Oxford, Oxford, UK.

Brain age is becoming a widely applied imaging-based biomarker of neural aging and potential proxy for brain integrity and health. We estimated multimodal and modality-specific brain age in the Whitehall II (WHII) MRI cohort using machine learning and imaging-derived measures of gray matter (GM) morphology, white matter microstructure (WM), and resting state functional connectivity (FC). The results showed that the prediction accuracy improved when multiple imaging modalities were included in the model (R = 0.30, 95% CI [0.24, 0.36]). The modality-specific GM and WM models showed similar performance (R = 0.22 [0.16, 0.27] and R = 0.24 [0.18, 0.30], respectively), while the FC model showed the lowest prediction accuracy (R = 0.002 [-0.005, 0.008]), indicating that the FC features were less related to chronological age compared to structural measures. Follow-up analyses showed that FC predictions were similarly low in a matched sub-sample from UK Biobank, and although FC predictions were consistently lower than GM predictions, the accuracy improved with increasing sample size and age range. Cardiovascular risk factors, including high blood pressure, alcohol intake, and stroke risk score, were each associated with brain aging in the WHII cohort. Blood pressure showed a stronger association with white matter compared to gray matter, while no differences in the associations of alcohol intake and stroke risk with these modalities were observed. In conclusion, machine-learning based brain age prediction can reduce the dimensionality of neuroimaging data to provide meaningful biomarkers of individual brain aging. However, model performance depends on study-specific characteristics including sample size and age range, which may cause discrepancies in findings across studies.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121758PMC
November 2020

Associations Between Longitudinal Trajectories of Cognitive and Social Activities and Brain Health in Old Age.

JAMA Netw Open 2020 08 3;3(8):e2013793. Epub 2020 Aug 3.

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.

Importance: Prior neuroimaging studies have found that late-life participation in cognitive (eg, reading) and social (eg, visiting friends and family) leisure activities are associated with magnetic resonance imaging (MRI) markers of the aging brain, but little is known about the neural and cognitive correlates of changes in leisure activities during the life span.

Objectives: To examine trajectories of cognitive and social activities from midlife to late life and evaluate whether these trajectories are associated with brain structure, functional connectivity, and cognition.

Design, Setting, And Participants: This prospective cohort included participants enrolled in the Whitehall II study and its MRI substudy based in the UK. Participants provided information on their leisure activities at 5 times during calendar years 1997 to 1999, 2002 to 2004, 2006, 2007 to 2009, and 2011 to 2013 and underwent MRI and cognitive battery testing from January 1, 2012, to December 31, 2016. Data analysis was performed from October 7, 2017, to July 15, 2019.

Main Outcome And Measures: Growth curve models and latent class growth analysis were used to identify longitudinal trajectories of cognitive and social activities. Multiple linear regression was used to evaluate associations between activity trajectories and gray matter, white matter microstructure, functional connectivity, and cognition.

Results: A total of 574 individuals (468 [81.5%] men; mean [SD] age, 69.9 [4.9] years; median Montreal Cognitive Assessment score, 28 [interquartile range, 26-28]) were included in the present analysis. During a mean (SD) of 15 (4.2) years, cognitive and social activity levels increased during midlife before reaching a plateau in late life. Both baseline (global cognition: unstandardized β [SE], 0.955 [0.285], uncorrected P = .001; executive function: β [SE], 1.831 [0.499], uncorrected P < .001; memory: β [SE], 1.394 [0.550], uncorrected P = .01; processing speed: β [SE], 1.514 [0.528], uncorrected P = .004) and change (global cognition: β [SE], -1.382 [0.492], uncorrected P = .005, executive function: β [SE], -2.219 [0.865], uncorrected P = .01; memory: β [SE], -2.355 [0.948], uncorrected P = .01) in cognitive activities were associated with multiple domains of cognition as well as global gray matter volume (β [SE], -0.910 [0.388], uncorrected P = .02). Baseline (β [SE], 1.695 [0.525], uncorrected P = .001) and change (β [SE], 2.542 [1.026], uncorrected P = .01) in social activities were associated only with executive function, in addition to voxelwise measures of functional connectivity that involved sensorimotor (quadratic change in social activities: number of voxels, 306; P = 0.01) and temporoparietal (linear change in social activities: number of voxels, 16; P = .02) networks. Otherwise, no voxelwise associations were found with gray matter, white matter, or resting-state functional connectivity. False discovery rate corrections for multiple comparisons suggested that the association between cognitive activity levels and executive function was robust (β [SE], 1.831 [0.499], false discovery rate P < .001).

Conclusions And Relevance: The findings suggest that a life course approach may delineate the association between leisure activities and cognitive and brain health and that interventions aimed at improving and maintaining cognitive engagement may be valuable for the cognitive health of community-dwelling older adults.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.13793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441365PMC
August 2020

Subjective Cognitive Complaints Given in Questionnaire: Relationship With Brain Structure, Cognitive Performance and Self-Reported Depressive Symptoms in a 25-Year Retrospective Cohort Study.

Am J Geriatr Psychiatry 2021 03 7;29(3):217-226. Epub 2020 Jul 7.

Department of Psychiatry (AT, SS, CA,EZ, NF, CES, AM, CEM, KPE), University of Oxford, Oxford, UK.

Background: Subjective cognitive complaints are common but it is unclear whether they indicate an underlying pathological process or reflect affective symptoms.

Method: 800 community-dwelling older adults were drawn from the Whitehall II cohort. Subjective cognitive complaint inquiry for memory and concentration, a range of neuropsychological tests and multimodal MRI were performed in 2012-2016. Subjective complaints were again elicited after 1 year. Group differences in grey and white matter, between those with and without subjective complaints, were assessed using voxel-based morphometry and tract-based spatial statistics, respectively. Mixed effects models assessed whether cognitive decline or depressive symptoms (over a 25-year period) were associated with later subjective complaints. Analyses were controlled for potential confounders and multiple comparisons.

Results: Mean age of the sample at scanning was 69.8 years (±5.1, range: 60.3-84.6). Subjective memory complaints were common (41%) and predicted further similar complaints later (mean 1.4 ± 1.4 years). There were no group differences in grey matter density or white matter integrity. Subjective complaints were not cross-sectionally or longitudinally associated with objectively assessed cognition. However, those with subjective complaints reported higher depressive symptoms ("poor concentration": odds ratio = 1.12, 95% CI 1.07-1.18; "poor memory": odds ratio = 1.18, 1.12-1.24).

Conclusions: In our sample subjective complaints were consistent over time and reflected depressive symptoms but not markers of neurodegenerative brain damage or concurrent or future objective cognitive impairment. Clinicians assessing patients presenting with memory complaints should be vigilant for affective disorders. These results question the rationale for including subjective complaints in a spectrum with Mild Cognitive Impairment diagnostic criteria.
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http://dx.doi.org/10.1016/j.jagp.2020.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097240PMC
March 2021

Sleep duration over 28 years, cognition, gray matter volume, and white matter microstructure: a prospective cohort study.

Sleep 2020 05;43(5)

Department of Neurology, Global Brain Health Institute, Memory and Aging Center, University of California, San Francisco, CA.

Study Objectives: To examine the association between sleep duration trajectories over 28 years and measures of cognition, gray matter volume, and white matter microstructure. We hypothesize that consistently meeting sleep guidelines that recommend at least 7 hours of sleep per night will be associated with better cognition, greater gray matter volumes, higher fractional anisotropy, and lower radial diffusivity values.

Methods: We studied 613 participants (age 42.3 ± 5.03 years at baseline) who self-reported sleep duration at five time points between 1985 and 2013, and who had cognitive testing and magnetic resonance imaging administered at a single timepoint between 2012 and 2016. We applied latent class growth analysis to estimate membership into trajectory groups based on self-reported sleep duration over time. Analysis of gray matter volumes was carried out using FSL Voxel-Based-Morphometry and white matter microstructure using Tract Based Spatial Statistics. We assessed group differences in cognitive and MRI outcomes using nonparametric permutation testing.

Results: Latent class growth analysis identified four trajectory groups, with an average sleep duration of 5.4 ± 0.2 hours (5%, N = 29), 6.2 ± 0.3 hours (37%, N = 228), 7.0 ± 0.2 hours (45%, N = 278), and 7.9 ± 0.3 hours (13%, N = 78). No differences in cognition, gray matter, and white matter measures were detected between groups.

Conclusions: Our null findings suggest that current sleep guidelines that recommend at least 7 hours of sleep per night may not be supported in relation to an association between sleep patterns and cognitive function or brain structure.
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http://dx.doi.org/10.1093/sleep/zsz290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215267PMC
May 2020

Multimodal MRI of grey matter, white matter, and functional connectivity in cognitively healthy mutation carriers at risk for frontotemporal dementia and Alzheimer's disease.

BMC Neurol 2019 Dec 27;19(1):343. Epub 2019 Dec 27.

Department of Radiology, Leiden University Medical Centre, Leiden, The Netherlands.

Background: Frontotemporal dementia (FTD) and Alzheimer's disease (AD) are associated with divergent differences in grey matter volume, white matter diffusion, and functional connectivity. However, it is unknown at what disease stage these differences emerge. Here, we investigate whether divergent differences in grey matter volume, white matter diffusion, and functional connectivity are already apparent between cognitively healthy carriers of pathogenic FTD mutations, and cognitively healthy carriers at increased AD risk.

Methods: We acquired multimodal magnetic resonance imaging (MRI) brain scans in cognitively healthy subjects with (n=39) and without (n=36) microtubule-associated protein Tau (MAPT) or progranulin (GRN) mutations, and with (n=37) and without (n=38) apolipoprotein E ε4 (APOE4) allele. We evaluated grey matter volume using voxel-based morphometry, white matter diffusion using tract-based spatial statistics (TBSS), and region-to-network functional connectivity using dual regression in the default mode network and salience network. We tested for differences between the respective carriers and controls, as well as for divergence of those differences. For the divergence contrast, we additionally performed region-of-interest TBSS analyses in known areas of white matter diffusion differences between FTD and AD (i.e., uncinate fasciculus, forceps minor, and anterior thalamic radiation).

Results: MAPT/GRN carriers did not differ from controls in any modality. APOE4 carriers had lower fractional anisotropy than controls in the callosal splenium and right inferior fronto-occipital fasciculus, but did not show grey matter volume or functional connectivity differences. We found no divergent differences between both carrier-control contrasts in any modality, even in region-of-interest analyses.

Conclusions: Concluding, we could not find differences suggestive of divergent pathways of underlying FTD and AD pathology in asymptomatic risk mutation carriers. Future studies should focus on asymptomatic mutation carriers that are closer to symptom onset to capture the first specific signs that may differentiate between FTD and AD.
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http://dx.doi.org/10.1186/s12883-019-1567-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933911PMC
December 2019

Large-scale intrinsic connectivity is consistent across varying task demands.

PLoS One 2019 10;14(4):e0213861. Epub 2019 Apr 10.

Institute of Cognitive Neuroscience, University College London, London, United Kingdom.

Measuring whole-brain functional connectivity patterns based on task-free ('resting-state') spontaneous fluctuations in the functional MRI (fMRI) signal is a standard approach to probing habitual brain states, independent of task-specific context. This view is supported by spatial correspondence between task- and rest-derived connectivity networks. Yet, it remains unclear whether intrinsic connectivity observed in a resting-state acquisition is persistent during task. Here, we sought to determine how changes in ongoing brain activation, elicited by task performance, impact the integrity of whole-brain functional connectivity patterns (commonly termed 'resting state networks'). We employed a 'steady-states' paradigm, in which participants continuously executed a specific task (without baseline periods). Participants underwent separate task-based (visual, motor and visuomotor) or task-free (resting) steady-state scans, each performed over a 5-minute period. This unique design allowed us to apply a set of traditional resting-state analyses to various task-states. In addition, a classical fMRI block-design was employed to identify individualized brain activation patterns for each task, allowing us to characterize how differing activation patterns across the steady-states impact whole-brain intrinsic connectivity patterns. By examining correlations across segregated brain regions (nodes) and the whole brain (using independent component analysis) using standard resting-state functional connectivity (FC) analysis, we show that the whole-brain network architecture characteristic of the resting-state is comparable across different steady-task states, despite striking inter-task changes in brain activation (signal amplitude). Changes in functional connectivity were detected locally, within the active networks. But to identify these local changes, the contributions of different FC networks to the global intrinsic connectivity pattern had to be isolated. Together, we show that intrinsic connectivity underlying the canonical resting-state networks is relatively stable even when participants are engaged in different tasks and is not limited to the resting-state.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213861PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457563PMC
December 2019

Predicting cognitive resilience from midlife lifestyle and multi-modal MRI: A 30-year prospective cohort study.

PLoS One 2019 19;14(2):e0211273. Epub 2019 Feb 19.

Department of Psychiatry, University of Oxford, Oxford, United Kingdom.

Background: There is significant heterogeneity in the clinical expression of structural brain abnormalities, including Alzheimer's disease biomarkers. Some individuals preserve their memory despite the presence of risk factors or pathological brain changes, indicating resilience. We aimed to test whether resilient individuals could be distinguished from those who develop cognitive impairment, using sociodemographic variables and neuroimaging.

Methods: We included 550 older adults participating in the Whitehall II study with longitudinal data, cognitive test results, and multi-modal MRI. Hippocampal atrophy was defined as Scheltens Scores >0. Resilient individuals (n = 184) were defined by high cognitive performance despite hippocampal atrophy (HA). Non-resilient participants (n = 133) were defined by low cognitive performance (≥1.5 standard deviations (S.D.) below the group mean) in the presence of HA. Dynamic and static exposures were evaluated for their ability to predict later resilience status using multivariable logistic regression. In a brain-wide analysis we tested for group differences in the integrity of white matter (structural connectivity) and resting-state networks (functional connectivity).

Findings: Younger age (OR: 0.87, 95% CI: 0.83 to 0.92, p<0.001), higher premorbid FSIQ (OR: 1.06, 95% CI: 1.03 to 1.10, p<0.0001) and social class (OR 1 vs. 3: 4.99, 95% CI: 1.30 to 19.16, p = 0.02, OR 2 vs. 3: 8.43, 95% CI: 1.80 to 39.45, p = 0.007) were independently associated with resilience. Resilient individuals could be differentiated from non-resilient participants by higher fractional anisotropy (FA), and less association between anterior and posterior resting state networks. Higher FA had a significantly more positive effect on cognitive performance in participants with HA, compared to those without.

Conclusions: Resilient individuals could be distinguished from those who developed impairments on the basis of sociodemographic characteristics, brain structural and functional connectivity, but not midlife lifestyles. There was a synergistic deleterious effect of hippocampal atrophy and poor white matter integrity on cognitive performance. Exploiting and supporting neural correlates of resilience could offer a fresh approach to postpone or avoid the appearance of clinical symptoms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211273PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380585PMC
November 2019

Association of Long-Term Diet Quality with Hippocampal Volume: Longitudinal Cohort Study.

Am J Med 2018 11 26;131(11):1372-1381.e4. Epub 2018 Jul 26.

Department of Epidemiology and Public Health, University College London, UK.

Background: Diet quality is associated with brain aging outcomes. However, few studies have explored in humans the brain structures potentially affected by long-term diet quality. We examined whether cumulative average of the Alternative Healthy Eating Index 2010 (AHEI-2010) score during adult life (an 11-year exposure period) is associated with hippocampal volume.

Methods: Analyses were based on data from 459 participants of the Whitehall II imaging sub-study (mean age [standard deviation] (SD) = 59.6 [5.3] years in 2002-2004, 19.2% women). Multimodal magnetic resonance imaging examination was performed at the end of follow-up (2015-2016). Structural images were acquired using a high-resolution 3-dimensional T1-weighted sequence and processed with Functional Magnetic Resonance Imaging of the Brain Software Library (FSL) tools. An automated model-based segmentation and registration tool was applied to extract hippocampal volumes.

Results: Higher AHEI-2010 cumulative average score (reflecting long-term healthy diet quality) was associated with a larger total hippocampal volume. For each 1 SD (SD = 8.7 points) increment in AHEI-2010 score, an increase of 92.5 mm (standard error = 42.0 mm) in total hippocampal volume was observed. This association was independent of sociodemographic factors, smoking habits, physical activity, cardiometabolic health factors, cognitive impairment, and depressive symptoms, and was more pronounced in the left hippocampus than in the right hippocampus. Of the AHEI-2010 components, no or light alcohol consumption was independently associated with larger hippocampal volume.

Conclusions: Higher long-term AHEI-2010 scores were associated with larger hippocampal volume. Accounting for the importance of hippocampal structures in several neuropsychiatric diseases, our findings reaffirm the need to consider adherence to healthy dietary recommendation in multi-interventional programs to promote healthy brain aging.
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http://dx.doi.org/10.1016/j.amjmed.2018.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237674PMC
November 2018

Encoding-related brain activity and accelerated forgetting in transient epileptic amnesia.

Cortex 2019 01 17;110:127-140. Epub 2018 May 17.

Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK. Electronic address:

The accelerated forgetting of newly learned information is common amongst patients with epilepsy and, in particular, in the syndrome of transient epileptic amnesia (TEA). However, the neural mechanisms underlying accelerated forgetting are poorly understood. It has been hypothesised that interictal epileptiform activity during longer retention intervals disrupts normally established memory traces. Here, we tested a distinct hypothesis-that accelerated forgetting relates to the abnormal encoding of memories. We studied a group of 15 patients with TEA together with matched, healthy control subjects. Despite normal performance on standard anterograde memory tasks, patients showed accelerated forgetting of a word list over one week. We used a subsequent memory paradigm to compare encoding-related brain activity in patients and controls. Participants studied a series of visually presented scenes whilst undergoing functional MRI scanning. Recognition memory for these scenes was then probed outside the scanner after delays of 45 min and of 4 days. Patients showed poorer memory for the scenes compared with controls. In the patients but not the controls, subsequently forgotten stimuli were associated with reduced hippocampal activation at encoding. Furthermore, patients demonstrated reduced deactivation of posteromedial cortex regions upon viewing subsequently remembered stimuli as compared to subsequently forgotten ones. These data suggest that abnormal encoding-related activity in key memory areas of the brain contributes to accelerated forgetting in TEA. We propose that abnormally encoded memory traces may be particularly vulnerable to interference from subsequently encountered material and hence be forgotten more rapidly. Our results shed light on the mechanisms underlying memory impairment in epilepsy, and offer support to the proposal that accelerated forgetting may be a useful marker of subtle dysfunction in memory-related brain systems.
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http://dx.doi.org/10.1016/j.cortex.2018.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335262PMC
January 2019

Peripheral DNA methylation, cognitive decline and brain aging: pilot findings from the Whitehall II imaging study.

Epigenomics 2018 05 25;10(5):585-595. Epub 2018 Apr 25.

Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.

Aim: The present study investigated the link between peripheral DNA methylation (DNAm), cognitive impairment and brain aging.

Methods: We tested the association between blood genome-wide DNAm profiles using the Illumina 450K arrays, cognitive dysfunction and brain MRI measures in selected participants of the Whitehall II imaging sub-study.

Results: Eight differentially methylated regions were associated with cognitive impairment. Accelerated aging based on the Hannum epigenetic clock was associated with mean diffusivity and global fractional anisotropy. We also identified modules of co-methylated loci associated with white matter hyperintensities. These co-methylation modules were enriched among pathways relevant to β-amyloid processing and glutamatergic signaling.

Conclusion: Our data support the notion that blood DNAm changes may have utility as a biomarker for cognitive dysfunction and brain aging.
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http://dx.doi.org/10.2217/epi-2017-0132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021930PMC
May 2018

Allostatic load as a predictor of grey matter volume and white matter integrity in old age: The Whitehall II MRI study.

Sci Rep 2018 04 23;8(1):6411. Epub 2018 Apr 23.

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JX, UK.

The allostatic load index quantifies the cumulative multisystem physiological response to chronic everyday stress, and includes cardiovascular, metabolic and inflammatory measures. Despite its central role in the stress response, research of the effect of allostatic load on the ageing brain has been limited. We investigated the relation of mid-life allostatic load index and multifactorial predictors of stroke (Framingham stroke risk) and diabetes (metabolic syndrome) with voxelwise structural grey and white matter brain integrity measures in the ageing Whitehall II cohort (N = 349, mean age = 69.6 (SD 5.2) years, N (male) = 281 (80.5%), mean follow-up before scan = 21.4 (SD 0.82) years). Higher levels of all three markers were significantly associated with lower grey matter density. Only higher Framingham stroke risk was significantly associated with lower white matter integrity (low fractional anisotropy and high mean diffusivity). Our findings provide some empirical support for the concept of allostatic load, linking the effect of everyday stress on the body with features of the ageing human brain.
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http://dx.doi.org/10.1038/s41598-018-24398-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913085PMC
April 2018

Exploring variability in basal ganglia connectivity with functional MRI in healthy aging.

Brain Imaging Behav 2018 Dec;12(6):1822-1827

Oxford Parkinson's Disease Centre (OPDC), Oxford, UK.

Changes in functional connectivity (FC) measured using resting state fMRI within the basal ganglia network (BGN) have been observed in pathologies with altered neurotransmitter systems and conditions involving motor control and dopaminergic processes. However, less is known about non-disease factors affecting FC in the BGN. The aim of this study was to examine associations of FC within the BGN with dopaminergic processes in healthy older adults. We explored the relationship between FC in the BGN and variables related to demographics, impulsive behavior, self-paced tasks, mood, and motor correlates in 486 participants in the Whitehall-II imaging sub-study using both region-of-interest- and voxel-based approaches. Age was the only correlate of FC in the BGN that was consistently significant with both analyses. The observed adverse effect of aging on FC may relate to alterations of the dopaminergic system, but no unique dopamine-related function seemed to have a link with FC beyond those detectable in and linearly correlated with healthy aging.
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http://dx.doi.org/10.1007/s11682-018-9824-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302142PMC
December 2018

Uncoupling protein 2 haplotype does not affect human brain structure and function in a sample of community-dwelling older adults.

PLoS One 2017 3;12(8):e0181392. Epub 2017 Aug 3.

Department of Psychiatry, University of Oxford, Oxford, United Kingdom.

Uncoupling protein 2 (UCP2) is a mitochondrial membrane protein that plays a role in uncoupling electron transport from adenosine triphosphate (ATP) formation. Polymorphisms of the UCP2 gene in humans affect protein expression and function and have been linked to survival into old age. Since UCP2 is expressed in several brain regions, we investigated in this study whether UCP2 polymorphisms might 1) affect occurrence of neurodegenerative or mental health disorders and 2) affect measures of brain structure and function. We used structural magnetic resonance imaging (MRI), diffusion-weighted MRI and resting-state functional MRI in the neuroimaging sub-study of the Whitehall II cohort. Data from 536 individuals aged 60 to 83 years were analyzed. No association of UCP2 polymorphisms with the occurrence of neurodegenerative disorders or grey and white matter structure or resting-state functional connectivity was observed. However, there was a significant effect on occurrence of mood disorders in men with the minor alleles of -866G>A (rs659366) and Ala55Val (rs660339)) being associated with increasing odds of lifetime occurrence of mood disorders in a dose dependent manner. This result was not accompanied by effects of UCP2 polymorphisms on brain structure and function, which might either indicate that the sample investigated here was too small and underpowered to find any significant effects, or that potential effects of UCP2 polymorphisms on the brain are too subtle to be picked up by any of the neuroimaging measures used.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181392PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542610PMC
September 2017

Distinct resting-state functional connections associated with episodic and visuospatial memory in older adults.

Neuroimage 2017 10 26;159:122-130. Epub 2017 Jul 26.

Department of Psychiatry, University of Oxford, Oxford, OX3 7JX, United Kingdom.

Episodic and spatial memory are commonly impaired in ageing and Alzheimer's disease. Volumetric and task-based functional magnetic resonance imaging (fMRI) studies suggest a preferential involvement of the medial temporal lobe (MTL), particularly the hippocampus, in episodic and spatial memory processing. The present study examined how these two memory types were related in terms of their associated resting-state functional architecture. 3T multiband resting state fMRI scans from 497 participants (60-82 years old) of the cross-sectional Whitehall II Imaging sub-study were analysed using an unbiased, data-driven network-modelling technique (FSLNets). Factor analysis was performed on the cognitive battery; the Hopkins Verbal Learning test and Rey-Osterreith Complex Figure test factors were used to assess verbal and visuospatial memory respectively. We present a map of the macroscopic functional connectome for the Whitehall II Imaging sub-study, comprising 58 functionally distinct nodes clustered into five major resting-state networks. Within this map we identified distinct functional connections associated with verbal and visuospatial memory. Functional anticorrelation between the hippocampal formation and the frontal pole was significantly associated with better verbal memory in an age-dependent manner. In contrast, hippocampus-motor and parietal-motor functional connections were associated with visuospatial memory independently of age. These relationships were not driven by grey matter volume and were unique to the respective memory domain. Our findings provide new insights into current models of brain-behaviour interactions, and suggest that while both episodic and visuospatial memory engage MTL nodes of the default mode network, the two memory domains differ in terms of the associated functional connections between the MTL and other resting-state brain networks.
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http://dx.doi.org/10.1016/j.neuroimage.2017.07.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678287PMC
October 2017

Associations between self-reported sleep quality and white matter in community-dwelling older adults: A prospective cohort study.

Hum Brain Mapp 2017 11 26;38(11):5465-5473. Epub 2017 Jul 26.

Department of Psychiatry, University of Oxford, Oxford, United Kingdom.

Both sleep disturbances and decline in white matter microstructure are commonly observed in ageing populations, as well as in age-related psychiatric and neurological illnesses. A relationship between sleep and white matter microstructure may underlie such relationships, but few imaging studies have directly examined this hypothesis. In a study of 448 community-dwelling members of the Whitehall II Imaging Sub-Study aged between 60 and 82 years (90 female, mean age 69.2 ± 5.1 years), we used the magnetic resonance imaging technique diffusion tensor imaging to examine the relationship between self-reported sleep quality and white matter microstructure. Poor sleep quality at the time of the diffusion tensor imaging scan was associated with reduced global fractional anisotropy and increased global axial diffusivity and radial diffusivity values, with small effect sizes. Voxel-wise analysis showed that widespread frontal-subcortical tracts, encompassing regions previously reported as altered in insomnia, were affected. Radial diffusivity findings remained significant after additional correction for demographics, general cognition, health, and lifestyle measures. No significant differences in general cognitive function, executive function, memory, or processing speed were detected between good and poor sleep quality groups. The number of times participants reported poor sleep quality over five time-points spanning a 16-year period was not associated with white matter measures. In conclusion, these data demonstrate that current sleep quality is linked to white matter microstructure. Small effect sizes may limit the extent to which poor sleep is a promising modifiable factor that may maintain, or even improve, white matter microstructure in ageing. Hum Brain Mapp 38:5465-5473, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/hbm.23739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655937PMC
November 2017

Moderate alcohol consumption as risk factor for adverse brain outcomes and cognitive decline: longitudinal cohort study.

BMJ 2017 Jun 6;357:j2353. Epub 2017 Jun 6.

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK.

 To investigate whether moderate alcohol consumption has a favourable or adverse association or no association with brain structure and function. Observational cohort study with weekly alcohol intake and cognitive performance measured repeatedly over 30 years (1985-2015). Multimodal magnetic resonance imaging (MRI) was performed at study endpoint (2012-15). Community dwelling adults enrolled in the Whitehall II cohort based in the UK (the Whitehall II imaging substudy). 550 men and women with mean age 43.0 (SD 5.4) at study baseline, none were "alcohol dependent" according to the CAGE screening questionnaire, and all safe to undergo MRI of the brain at follow-up. Twenty three were excluded because of incomplete or poor quality imaging data or gross structural abnormality (such as a brain cyst) or incomplete alcohol use, sociodemographic, health, or cognitive data. Structural brain measures included hippocampal atrophy, grey matter density, and white matter microstructure. Functional measures included cognitive decline over the study and cross sectional cognitive performance at the time of scanning. Higher alcohol consumption over the 30 year follow-up was associated with increased odds of hippocampal atrophy in a dose dependent fashion. While those consuming over 30 units a week were at the highest risk compared with abstainers (odds ratio 5.8, 95% confidence interval 1.8 to 18.6; P≤0.001), even those drinking moderately (14-21 units/week) had three times the odds of right sided hippocampal atrophy (3.4, 1.4 to 8.1; P=0.007). There was no protective effect of light drinking (1-<7 units/week) over abstinence. Higher alcohol use was also associated with differences in corpus callosum microstructure and faster decline in lexical fluency. No association was found with cross sectional cognitive performance or longitudinal changes in semantic fluency or word recall. Alcohol consumption, even at moderate levels, is associated with adverse brain outcomes including hippocampal atrophy. These results support the recent reduction in alcohol guidance in the UK and question the current limits recommended in the US.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460586PMC
http://dx.doi.org/10.1136/bmj.j2353DOI Listing
June 2017

Quantitative FLAIR MRI in Amyotrophic Lateral Sclerosis.

Acad Radiol 2017 10 29;24(10):1187-1194. Epub 2017 May 29.

Centre for Functional Magnetic Resonance Imaging of the Brain, Oxford University, John Radcliffe Hospital, West Wing Level 6, Oxford OX3 9DU, UK; Nuffield Department of Clinical Neurosciences, Oxford University, John Radcliffe Hospital, West Wing Level 6, Oxford OX3 9DU, UK; Oxford University Centre for Magnetic Resonance Research, John Radcliffe Hospital, West Wing Level 6, Oxford OX3 9DU, UK. Electronic address:

Rationale And Objectives: T2-weighted magnetic resonance imaging (MRI) hyperintensity assessed visually in the corticospinal tract (CST) lacks sensitivity for a diagnosis of amyotrophic lateral sclerosis (ALS). We sought to explore a quantitative approach to fluid-attenuated inversion recovery (FLAIR) MRI intensity across a range of ALS phenotypes.

Materials And Methods: Thirty-three classical ALS patients, 10 with a flail arm presentation, and six with primary lateral sclerosis underwent MRI at 3 Tesla. Comparisons of quantitative FLAIR intensity in the CST and corpus callosum were made between 21 healthy controls and within patient phenotypic subgroups, some of whom were studied longitudinally.

Results: Mean FLAIR intensity was greater in patient groups. The cerebral peduncle intensity provided the strongest subgroup classification. FLAIR intensity increased longitudinally. The rate of change of FLAIR within CST correlated with rate of decline in executive function and ALS functional rating score.

Conclusions: FLAIR MRI encodes quantifiable information of potential diagnostic, stratification, and monitoring value.
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http://dx.doi.org/10.1016/j.acra.2017.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605225PMC
October 2017

Reduced Resting-State Functional Connectivity in Current and Recovered Restrictive Anorexia Nervosa.

Front Psychiatry 2017 28;8:30. Epub 2017 Mar 28.

Department of Psychiatry, University of Oxford and Oxford Health NHS Foundation Trust, Warneford Hospital , Oxford , UK.

Functional connectivity studies based on resting-state functional magnetic resonance imaging (rs-fMRI) have shown alterations in brain networks associated with self-referential processing, cognitive control, and somatosensory processing in anorexia nervosa (AN). This study aimed to further investigate the functional connectivity of resting-state networks (RSNs) in homogenous subsamples of individuals with restrictive AN (current and recovered) and the relationship this has with core eating disorder psychopathology. rs-fMRI scans were obtained from 12 female individuals with restrictive AN, 14 females recovered from restrictive AN, and 16 female healthy controls. Independent components analysis revealed a set of functionally relevant RSNs, previously reported in the literature. Dual regression analysis showed decreased temporal coherence within the lateral visual and auditory RSNs in individuals with current AN and those recovered from AN compared to healthy individuals. This decreased connectivity was also found in regions associated with somatosensory processing, and is consistent with reduced interoceptive awareness and body image perception, characteristic of AN. Widespread gray matter (GM) reductions were also found in both the AN groups, and differences in functional connectivity were no longer significant when GM maps were added as a covariate in the dual regression analysis. This raises the possibility that deficits in somatosensory and interoceptive processing observed in AN may be in part underpinned or exacerbated by GM reductions.
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http://dx.doi.org/10.3389/fpsyt.2017.00030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5368282PMC
March 2017

Effect of age and the APOE gene on metabolite concentrations in the posterior cingulate cortex.

Neuroimage 2017 05 18;152:509-516. Epub 2017 Mar 18.

Department of Psychiatry, University of Oxford, Oxford OX3 7JX, United Kingdom.

Proton magnetic resonance spectroscopy (H-MRS) has provided valuable information about the neurochemical profile of Alzheimer's disease (AD). However, its clinical utility has been limited in part by the lack of consistent information on how metabolite concentrations vary in the normal aging brain and in carriers of apolipoprotein E (APOE) ε4, an established risk gene for AD. We quantified metabolites within an 8cm voxel within the posterior cingulate cortex (PCC)/precuneus in 30 younger (20-40 years) and 151 cognitively healthy older individuals (60-85 years). All H-MRS scans were performed at 3T using the short-echo SPECIAL sequence and analyzed with LCModel. The effect of APOE was assessed in a sub-set of 130 volunteers. Older participants had significantly higher myo-inositol and creatine, and significantly lower glutathione and glutamate than younger participants. There was no significant effect of APOE or an interaction between APOE and age on the metabolite profile. Our data suggest that creatine, a commonly used reference metabolite in H-MRS studies, does not remain stable across adulthood within this region and therefore may not be a suitable reference in studies involving a broad age-range. Increases in creatine and myo-inositol may reflect age-related glial proliferation; decreases in glutamate and glutathione suggest a decline in synaptic and antioxidant efficiency. Our findings inform longitudinal clinical studies by characterizing age-related metabolite changes in a non-clinical sample.
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http://dx.doi.org/10.1016/j.neuroimage.2017.03.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440729PMC
May 2017

Classification and characterization of periventricular and deep white matter hyperintensities on MRI: A study in older adults.

Neuroimage 2018 04 15;170:174-181. Epub 2017 Mar 15.

Centre for the functional MRI of the Brain (FMRIB), University of Oxford, UK; Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze, Università di Modena e Reggio Emilia, Italy.

White matter hyperintensities (WMH) are frequently divided into periventricular (PWMH) and deep (DWMH), and the two classes have been associated with different cognitive, microstructural, and clinical correlates. However, although this distinction is widely used in visual ratings scales, how to best anatomically define the two classes is still disputed. In fact, the methods used to define PWMH and DWMH vary significantly between studies, making results difficult to compare. The purpose of this study was twofold: first, to compare four current criteria used to define PWMH and DWMH in a cohort of healthy older adults (mean age: 69.58 ± 5.33 years) by quantifying possible differences in terms of estimated volumes; second, to explore associations between the two WMH sub-classes with cognition, tissue microstructure and cardiovascular risk factors, analysing the impact of different criteria on the specific associations. Our results suggest that the classification criterion used for the definition of PWMH and DWMH should not be considered a major obstacle for the comparison of different studies. We observed that higher PWMH load is associated with reduced cognitive function, higher mean arterial pressure and age. Higher DWMH load is associated with higher body mass index. PWMH have lower fractional anisotropy than DWMH, which also have more heterogeneous microstructure. These findings support the hypothesis that PWMH and DWMH are different entities and that their distinction can provide useful information about healthy and pathological aging processes.
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http://dx.doi.org/10.1016/j.neuroimage.2017.03.024DOI Listing
April 2018
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