Publications by authors named "Claire E Sexton"

44 Publications

Alzheimer's disease research progress in Australia: The Alzheimer's Association International Conference Satellite Symposium in Sydney.

Alzheimers Dement 2021 May 31. Epub 2021 May 31.

Departments of Neuroscience and Neurology, Center for Translational Research in Neurodegenerative Disease, Normal Fixel Center for Neurological Diseases, University of Florida College of Medicine, Gainesville, Florida, USA.

The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sydney, Australia in 2019, highlighting the leadership of Australian researchers in advancing the understanding of and treatment developments for Alzheimer's disease (AD) and other dementias. This leadership includes the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL), which has fueled the identification and development of many biomarkers and novel therapeutics. Two multimodal lifestyle intervention studies have been launched in Australia; and Australian researchers have played leadership roles in other global studies in diverse populations. Australian researchers have also played an instrumental role in efforts to understand mechanisms underlying vascular contributions to cognitive impairment and dementia; and through the Women's Healthy Aging Project have elucidated hormonal and other factors that contribute to the increased risk of AD in women. Alleviating the behavioral and psychological symptoms of dementia has also been a strong research and clinical focus in Australia.
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http://dx.doi.org/10.1002/alz.12380DOI Listing
May 2021

Self-Reported Sleep Relates to Microstructural Hippocampal Decline in β-Amyloid Positive Adults Beyond Genetic Risk.

Sleep 2021 Apr 27. Epub 2021 Apr 27.

Research Group for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, 0317 Oslo, Norway.

Study Objectives: A critical role linking sleep with memory decay and β-amyloid (Aβ) accumulation, two markers of Alzheimer's disease (AD) pathology, may be played by hippocampal integrity. We tested the hypotheses that worse self-reported sleep relates to decline in memory and intra-hippocampal microstructure, including in the presence of Aβ.

Methods: Two-hundred and forty-three cognitively healthy participants, aged 19-81 years, completed the Pittsburgh Sleep Quality Index once, and 2 diffusion tensor imaging sessions, on average 3 years apart, allowing measures of decline in intra-hippocampal microstructure as indexed by increased mean diffusivity. We measured memory decay at each imaging session using verbal delayed recall. One session of positron emission tomography, in 108 participants above 44 years of age, yielded 23 Aβ positive. Genotyping enabled control for APOE ε4 status, and polygenic scores for sleep and AD, respectively.

Results: Worse global sleep quality and sleep efficiency related to more rapid reduction of hippocampal microstructure over time. Focusing on efficiency (the percentage of time in bed at night spent asleep), the relation was stronger in presence of Aβ accumulation, and hippocampal integrity decline mediated the relation with memory decay. The results were not explained by genetic risk for sleep efficiency or AD.

Conclusions: Worse sleep efficiency related to decline in hippocampal microstructure, especially in the presence of Aβ accumulation, and Aβ might link poor sleep and memory decay. As genetic risk did not account for the associations, poor sleep efficiency might constitute a risk marker for AD, although the driving causal mechanisms remain unknown.
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http://dx.doi.org/10.1093/sleep/zsab110DOI Listing
April 2021

Poor Self-Reported Sleep is Related to Regional Cortical Thinning in Aging but not Memory Decline-Results From the Lifebrain Consortium.

Cereb Cortex 2021 Mar;31(4):1953-1969

Center for Lifespan Changes in Brain and Cognition, University of Oslo, 0315 Oslo, Norway.

We examined whether sleep quality and quantity are associated with cortical and memory changes in cognitively healthy participants across the adult lifespan. Associations between self-reported sleep parameters (Pittsburgh Sleep Quality Index, PSQI) and longitudinal cortical change were tested using five samples from the Lifebrain consortium (n = 2205, 4363 MRIs, 18-92 years). In additional analyses, we tested coherence with cell-specific gene expression maps from the Allen Human Brain Atlas, and relations to changes in memory performance. "PSQI # 1 Subjective sleep quality" and "PSQI #5 Sleep disturbances" were related to thinning of the right lateral temporal cortex, with lower quality and more disturbances being associated with faster thinning. The association with "PSQI #5 Sleep disturbances" emerged after 60 years, especially in regions with high expression of genes related to oligodendrocytes and S1 pyramidal neurons. None of the sleep scales were related to a longitudinal change in episodic memory function, suggesting that sleep-related cortical changes were independent of cognitive decline. The relationship to cortical brain change suggests that self-reported sleep parameters are relevant in lifespan studies, but small effect sizes indicate that self-reported sleep is not a good biomarker of general cortical degeneration in healthy older adults.
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http://dx.doi.org/10.1093/cercor/bhaa332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945023PMC
March 2021

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

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

A critical evaluation of systematic reviews assessing the effect of chronic physical activity on academic achievement, cognition and the brain in children and adolescents: a systematic review.

Int J Behav Nutr Phys Act 2020 06 22;17(1):79. Epub 2020 Jun 22.

Wellcome Centre for Integrative Neuroimaging, Oxford Centre for Human Brain Activity, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JX, UK.

Background: International and national committees have started to evaluate the evidence for the effects of physical activity on neurocognitive health in childhood and adolescence to inform policy. Despite an increasing body of evidence, such reports have shown mixed conclusions. We aimed to critically evaluate and synthesise the evidence for the effects of chronic physical activity on academic achievement, cognitive performance and the brain in children and adolescents in order to guide future research and inform policy.

Methods: MedLine, Embase, PsycINFO, Cochrane Library, Web of Science, and ERIC electronic databases were searched from inception to February 6th, 2019. Articles were considered eligible for inclusion if they were systematic reviews with or without meta-analysis, published in peer-reviewed (English) journals. Reviews had to be on school-aged children and/or adolescents that reported on the effects of chronic physical activity or exercise interventions, with cognitive markers, academic achievement or brain markers as outcomes. Reviews were selected independently by two authors and data were extracted using a pre-designed data extraction template. The quality of reviews was assessed using AMSTAR-2 criteria.

Results: Of 908 retrieved, non-duplicated articles, 19 systematic reviews met inclusion criteria. One high-quality review reported inconsistent evidence for physical activity-related effects on cognitive- and academic performance in obese or overweight children and adolescents. Eighteen (critically) low-quality reviews presented mixed favourable and null effects, with meta-analyses showing small effect sizes (0.1-0.3) and high heterogeneity. Low-quality reviews suggested physical activity-related brain changes, but lacked an interpretation of these findings. Systematic reviews varied widely in their evidence synthesis, rarely took intervention characteristics (e.g. dose), intervention fidelity or study quality into account and suspected publication bias. Reviews consistently reported that there is a lack of high-quality studies, of studies that include brain imaging outcomes, and of studies that include adolescents or are conducted in South American and African countries.

Conclusions: Inconsistent evidence exists for chronic physical activity-related effects on cognitive-, academic-, and brain outcomes. The field needs to refocus its efforts towards improving study quality, transparency of reporting and dissemination, and is urged to differentiate between intervention characteristics for its findings to have a meaningful impact on policy.
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http://dx.doi.org/10.1186/s12966-020-00959-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310146PMC
June 2020

The effects of an aerobic training intervention on cognition, grey matter volumes and white matter microstructure.

Physiol Behav 2020 09 29;223:112923. Epub 2020 May 29.

FMRIB Centre, Wellcome Centre for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK, OX3 9DU. Electronic address:

While there is strong evidence from observational studies that physical activity is associated with reduced risk of cognitive decline and dementia, the extent to which aerobic training interventions impact on cognitive health and brain structure remains subject to debate. In a pilot study of 46 healthy older adults (66.6 years ± 5.2 years, 63% female), we compared the effects of a twelve-week aerobic training programme to a waitlist control condition on cardiorespiratory fitness, cognition and magnetic resonance imaging (MRI) outcomes. Cardiorespiratory fitness was assessed by VO max testing. Cognitive assessments spanned executive function, memory and processing speed. Structural MRI analysis included examination of hippocampal volume, and voxel-wise assessment of grey matter volumes using voxel-based morphometry. Diffusion tensor imaging analysis of fractional anisotropy, axial diffusivity and radial diffusivity was performed using tract-based spatial statistics. While the intervention successfully increased cardiorespiratory fitness, there was no evidence that the aerobic training programme led to changes in cognitive functioning or measures of brain structure in older adults. Interventions that are longer lasting, multi-factorial, or targeted at specific high-risk populations, may yield more encouraging results.
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http://dx.doi.org/10.1016/j.physbeh.2020.112923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378567PMC
September 2020

The effects of digital cognitive behavioral therapy for insomnia on cognitive function: a randomized controlled trial.

Sleep 2020 09;43(9)

Oxford Centre for Human Brain Activity, Wellcome Centre for Integrative Neuroimaging, Department of Psychiatry, University of Oxford, Oxford, UK.

Study Objectives: We sought to examine the impact of digital cognitive behavioral therapy (dCBT) for insomnia on both self-reported cognitive impairment and objective cognitive performance.

Methods: The Defining the Impact of Sleep improvement on Cognitive Outcomes (DISCO) trial was an online, two-arm, single-blind, randomized clinical trial of dCBT versus wait-list control. Participants were aged 25 years and older, met DSM-5 diagnostic criteria for insomnia disorder, and reported difficulties with concentration or memory. Assessments were carried out online at baseline, and 10 and 24 weeks post-randomization. The primary outcome measure was self-reported cognitive impairment, assessed with the British Columbia Cognitive Complaints Inventory (BC-CCI). Secondary outcomes included tests of cognitive performance, insomnia symptoms, cognitive failures, fatigue, sleepiness, depression, and anxiety.

Results: Four hundred and ten participants with insomnia were recruited and assigned to dCBT (N = 205) or wait-list control (N = 205). At 10 weeks post-randomization the estimated adjusted mean difference for the BC-CCI was -3.03 (95% CI: -3.60, -2.47; p < 0.0001, d = -0.86), indicating that participants in the dCBT group reported less cognitive impairment than the control group. These effects were maintained at 24 weeks (d = -0.96) and were mediated, in part, via reductions in insomnia severity and increased sleep efficiency. Treatment effects in favor of dCBT, at both 10 and 24 weeks, were found for insomnia severity, sleep efficiency, cognitive failures, fatigue, sleepiness, depression, and anxiety. We found no between-group differences in objective tests of cognitive performance.

Conclusions: Our study shows that dCBT robustly decreases self-reported cognitive impairment at post-treatment and these effects are maintained at 6 months.
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http://dx.doi.org/10.1093/sleep/zsaa034DOI Listing
September 2020

Alcohol consumption is associated with reduced creatine levels in the hippocampus of older adults.

Psychiatry Res Neuroimaging 2020 01 16;295:111019. Epub 2019 Nov 16.

Department of Psychiatry, University of Oxford, Oxford, UK; Global Brain Health Institute, Department of Neurology, University of California San Francisco, San Francisco, California, USA.

Besides its well established susceptibility to ageing, the hippocampus has also been shown to be affected by alcohol consumption. Proton spectroscopy (H-MRS) of the hippocampus, particularly at high-field 7T MRI, may further our understanding of these associations. Here, we aimed to examine how hippocampal metabolites varied with age and alcohol consumption. Hippocampal metabolite spectra were acquired in 37 older adults using 7T H-MRS, from which we determined the absolute concentration of N-acetylaspartate (NAA), creatine, choline, myo-inositol, glutamate and glutamine. Thirty participants (mean age = 70.4 ± 4.7 years) also had self-reported data on weekly alcohol consumption. Total choline inversely correlated with age, although this did not survive multiple comparisons correction. Crucially, adults with a higher weekly alcohol consumption had significantly lower levels of creatine, suggesting a deficit in their hippocampal metabolism. These findings add to an increasing body of evidence linking alcohol to hippocampal function.
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http://dx.doi.org/10.1016/j.pscychresns.2019.111019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961205PMC
January 2020

Self-reported sleep relates to hippocampal atrophy across the adult lifespan: results from the Lifebrain consortium.

Sleep 2020 05;43(5)

Center for Lifespan Changes in Brain and Cognition, University of Oslo, Norway.

Objectives: Poor sleep is associated with multiple age-related neurodegenerative and neuropsychiatric conditions. The hippocampus plays a special role in sleep and sleep-dependent cognition, and accelerated hippocampal atrophy is typically seen with higher age. Hence, it is critical to establish how the relationship between sleep and hippocampal volume loss unfolds across the adult lifespan.

Methods: Self-reported sleep measures and MRI-derived hippocampal volumes were obtained from 3105 cognitively normal participants (18-90 years) from major European brain studies in the Lifebrain consortium. Hippocampal volume change was estimated from 5116 MRIs from 1299 participants for whom longitudinal MRIs were available, followed up to 11 years with a mean interval of 3.3 years. Cross-sectional analyses were repeated in a sample of 21,390 participants from the UK Biobank.

Results: No cross-sectional sleep-hippocampal volume relationships were found. However, worse sleep quality, efficiency, problems, and daytime tiredness were related to greater hippocampal volume loss over time, with high scorers showing 0.22% greater annual loss than low scorers. The relationship between sleep and hippocampal atrophy did not vary across age. Simulations showed that the observed longitudinal effects were too small to be detected as age-interactions in the cross-sectional analyses.

Conclusions: Worse self-reported sleep is associated with higher rates of hippocampal volume decline across the adult lifespan. This suggests that sleep is relevant to understand individual differences in hippocampal atrophy, but limited effect sizes call for cautious interpretation.
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http://dx.doi.org/10.1093/sleep/zsz280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215271PMC
May 2020

Connections Between Insomnia and Cognitive Aging.

Neurosci Bull 2020 Jan 20;36(1):77-84. Epub 2019 Jun 20.

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

Insomnia is a common sleep disorder among older adults, and a risk factor for poor physical and mental health. However, the relationship between insomnia and cognitive health is not well understood. Here, we review observational studies that have investigated whether insomnia is associated with deficits in objective cognitive performance and an increased risk of dementia, magnetic resonance imaging studies that have assessed grey matter volumes and white matter microstructure, and interventional studies that have explored whether the treatment of insomnia can improve cognitive outcomes. There are inconsistent findings regarding impaired performance in objective cognitive tests and reduced grey matter volumes, and limited, emerging, evidence that suggests that insomnia is associated with an increased risk of dementia and reduced white matter integrity. Although the interventional literature is still in its infancy, there is some indication that treatment may have an impact on vigilance. Well-powered studies examining sources of heterogeneity are warranted.
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http://dx.doi.org/10.1007/s12264-019-00401-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940406PMC
January 2020

Population-Based Approaches to Dementia Prevention.

J Alzheimers Dis 2019 ;70(s1):S15-S17

Department of Psychiatry, Neurology, and Epidemiology, Global Brain Health Institute, University of California, San Francisco, San Francisco, CA, USA.

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http://dx.doi.org/10.3233/JAD-190104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700612PMC
October 2020

Associations between modifiable risk factors and white matter of the aging brain: insights from diffusion tensor imaging studies.

Neurobiol Aging 2019 08 11;80:56-70. Epub 2019 Apr 11.

Department of Neurology, Global Brain Health Institute, Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA; Department of Psychiatry, Wellcome Centre for Integrative Neuroscience, Oxford Centre for Human Brain Activity, University of Oxford, John Radcliffe Hospital, UK. Electronic address:

There is increasing interest in factors that may modulate white matter (WM) breakdown and, consequentially, age-related cognitive and behavioral deficits. Recent diffusion tensor imaging studies have examined the relationship of such factors with WM microstructure. This review summarizes the evidence regarding the relationship between WM microstructure and recognized modifiable factors, including hearing loss, hypertension, diabetes, obesity, smoking, depressive symptoms, physical (in) activity, and social isolation, as well as sleep disturbances, diet, cognitive training, and meditation. Current cross-sectional evidence suggests a clear link between loss of WM integrity (lower fractional anisotropy and higher mean diffusivity) and hypertension, obesity, diabetes, and smoking; a relationship that seems to hold for hearing loss, social isolation, depressive symptoms, and sleep disturbances. Physical activity, cognitive training, diet, and meditation, on the other hand, may protect WM with aging. Preliminary evidence from cross-sectional studies of treated risk factors suggests that modification of factors could slow down negative effects on WM microstructure. Careful intervention studies are needed for this literature to contribute to public health initiatives going forward.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683729PMC
August 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 between gait and cognition in an elderly population based sample.

Gait Posture 2018 09 29;65:240-245. Epub 2018 Jul 29.

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

Background: Gait is thought to have a cognitive component, but the current evidence in healthy elderly is mixed. We studied the association between multiple gait and cognitive measures in a cohort of older people.

Methods: One hundred and seventy-eight cognitively healthy participants from the Whitehall II Imaging Sub-study had a detailed clinical and neuropsychological assessment, as well as an MRI scan. Spatiotemporal and variability gait measures were derived from two 10 m walks at self-selected speed. We did a linear regression analysis, entering potential confounders with backwards elimination of variables with p ≥ 0.1. The remaining variables were then entered into a second regression before doing a stepwise analysis of cognitive measures, entering variables with p < 0.05 and removing those with p ≥ 0.1.

Results: Amongst absolute gait measures, only greater stride length was associated with better performance on the Trail Making Test A (p = 0.023) and the Boston Naming Test (p = 0.042). The stride time variability was associated with performance on the Trail Making Test A (p = 0.031). Age was associated with poorer walking speed (p = 0.014) and stride time (p = 0.011), female sex with shorter stride time (p = 0.000) and shorter double stance (p = 0.005). Length of full-time education was associated with faster walking speed (p = 0.012) and shorter stride time (p = 0.045), and a history of muscular-skeletal disease with slower walking speed (p = 0.01) and shorter stride length (p = 0.015). Interestingly, volume of white matter hyperintensities (WMH) on FLAIR MRI images did not contribute independently to any of the gait measures (p > 0.05).

Conclusions: No strong relationship between gait and non-motor cognition was observed in a cognitively healthy, high functioning sample of elderly. Nevertheless, we found some relationships with spatial, but not temporal gait which warrant further investigation. WMH made no independent contributionto gait.
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http://dx.doi.org/10.1016/j.gaitpost.2018.07.178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109203PMC
September 2018

Cognition and mobility show a global association in middle- and late-adulthood: Analyses from the Canadian Longitudinal Study on Aging.

Gait Posture 2018 07 19;64:238-243. Epub 2018 Jun 19.

Wellcome Centre for Integrative Neuroimaging, Oxford Centre for Human Brain Activity, Department of Psychiatry, University of Oxford, Oxford, United Kingdom; Global Brain Health Institute, Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA. Electronic address:

Background: Given our aging population, there's great interest in identifying modifiable risk factors for cognitive decline. Studies have highlighted the relationship between aspects of mobility and cognitive processes. However, cognition and mobility are both multifaceted concepts and their interrelationships remain to be well defined.

Research Question: Here, we firstly aimed to replicate cross-sectional associations between objective measures of mobility and cognition. Second, we tested whether these associations remained after the consideration of multiple age-related confounders. Finally, to test the hypothesis that the association between mobility and cognition is stronger in older adults, we examined the moderating effect of age in the association between mobility and cognition.

Methods: In the Canadian Longitudinal Study on Aging, 28,808 community-dwelling adults (aged 45-87; 51% female) completed mobility (gait, balance and chair stands) and cognitive (memory, executive function and processing speed) assessments. General linear models were used to examine mobility-cognition relationships and the moderating effect of age.

Results: Cognitive measures were significantly associated with mobility measures (all p < 0.001). Further, age significantly moderated the mobility-cognition relationship, with the strength of the associations generally increasing with age.

Significance: All cognitive measures were related to indices of mobility, suggesting a global association. In our moderation analyses, the mobility-cognition relationship often increased with age. However, the small effect sizes observed suggest that mobility is, in isolation, not a strong correlate of cognitive performance in middle and late-adulthood.
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http://dx.doi.org/10.1016/j.gaitpost.2018.06.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052573PMC
July 2018

A community-based physical activity intervention to prevent mobility-related disability for retired older people (REtirement in ACTion (REACT)): study protocol for a randomised controlled trial.

Trials 2018 Apr 17;19(1):228. Epub 2018 Apr 17.

Centre for Exercise, Nutrition and Health Sciences, School for Policy Studies, University of Bristol, Bristol, BS8 1TZ, UK.

Background: The REtirement in ACTion (REACT) study is a multi-centre, pragmatic, two-arm, parallel-group randomised controlled trial (RCT) with an internal pilot phase. It aims to test the effectiveness and cost-effectiveness of a community, group-based physical activity intervention for reducing, or reversing, the progression of functional limitations in older people who are at high risk of mobility-related disability.

Methods/design: A sample of 768 sedentary, community-dwelling, older people aged 65 years and over with functional limitations, but who are still ambulatory (scores between 4 and 9 out of 12 in the Short Physical Performance Battery test (SPPB)) will be randomised to receive either the REACT intervention, delivered over a period of 12 months by trained facilitators, or a minimal control intervention. The REACT study incorporates comprehensive process and economic evaluation and a nested sub-study which will test the hypothesis that the REACT intervention will slow the rate of brain atrophy and of decline in cognitive function assessed using magnetic resonance imaging (MRI). Outcome data will be collected at baseline, 6, 12 and 24 months for the main study, with MRI sub-study data collected at baseline, 6 and 12 months. The primary outcome analysis (SPPB score at 24 months) will be undertaken blinded to group allocation. Primary comparative analyses will be on an intention-to-treat (ITT) basis with due emphasis placed on confidence intervals.

Discussion: REACT represents the first large-scale, pragmatic, community-based trial in the UK to target the non-disabled but high-risk segment of the older population with an intervention to reduce mobility-related disability. A programme that can successfully engage this population in sufficient activity to improve strength, aerobic capacity, coordination and balance would have a major impact on sustaining health and independence. REACT is also the first study of its kind to conduct a full economic and comprehensive process evaluation alongside the RCT. If effective and cost-effective, the REACT intervention has strong potential to be implemented widely in the UK and elsewhere.

Trial Registration: ISRCTN, ID: ISRCTN45627165 . Retrospectively registered on 13 June 2016. Trial sponsor: University of Bath. Protocol Version 1.5.
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http://dx.doi.org/10.1186/s13063-018-2603-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905123PMC
April 2018

Sleep and cognitive performance: cross-sectional associations in the UK Biobank.

Sleep Med 2017 Oct 14;38:85-91. Epub 2017 Jul 14.

Clinic for Psychiatry and Psychotherapy, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.

Objective: The relationship between insomnia symptoms and cognitive performance is unclear, particularly at the population level. We conducted the largest examination of this association to date through analysis of the UK Biobank, a large population-based sample of adults aged 40-69 years. We also sought to determine associations between cognitive performance and self-reported chronotype, sleep medication use and sleep duration.

Methods: This cross-sectional, population-based study involved 477,529 participants, comprising 133,314 patients with frequent insomnia symptoms (age: 57.4 ± 7.7 years; 62.1% female) and 344,215 controls without insomnia symptoms (age: 56.1 ± 8.2 years; 52.0% female). Cognitive performance was assessed by a touchscreen test battery probing reasoning, basic reaction time, numeric memory, visual memory, and prospective memory. Adjusted models included relevant demographic, clinical, and sleep variables.

Results: Frequent insomnia symptoms were associated with cognitive impairment in unadjusted models; however, these effects were reversed after full adjustment, leaving those with frequent insomnia symptoms showing statistically better cognitive performance over those without. Relative to intermediate chronotype, evening chronotype was associated with superior task performance, while morning chronotype was associated with the poorest performance. Sleep medication use and both long (>9 h) and short (<7 h) sleep durations were associated with impaired performance.

Conclusions: Our results suggest that after adjustment for potential confounding variables, frequent insomnia symptoms may be associated with a small statistical advantage, which is unlikely to be clinically meaningful, on simple neurocognitive tasks. Further work is required to examine the mechanistic underpinnings of an apparent evening chronotype advantage in cognitive performance and the impairment associated with morning chronotype, sleep medication use, and sleep duration extremes.
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http://dx.doi.org/10.1016/j.sleep.2017.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930168PMC
October 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

Effects of digital Cognitive Behavioural Therapy for Insomnia on cognitive function: study protocol for a randomised controlled trial.

Trials 2017 06 17;18(1):281. Epub 2017 Jun 17.

Oxford Nuffield Department of Clinical Neurosciences, Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB Centre), University of Oxford, Oxford, UK.

Background: The daytime effects of insomnia pose a significant burden to patients and drive treatment seeking. In addition to subjective deficits, meta-analytic data show that patients experience reliable objective impairments across several cognitive domains. While Cognitive Behavioural Therapy for Insomnia (CBT-I) is an effective and scalable treatment, we know little about its impact upon cognitive function. Trials of CBT-I have typically used proxy measures for cognitive functioning, such as fatigue or work performance scales, and no study has assessed self-reported impairment in cognitive function as a primary outcome. Moreover, only a small number of studies have assessed objective cognitive performance, pre-to-post CBT-I, with mixed results. This study specifically aims to (1) investigate the impact of CBT-I on cognitive functioning, assessed through both self-reported impairment and objective performance measures, and (2) examine whether change in sleep mediates this impact.

Methods/design: We propose a randomised controlled trial of 404 community participants meeting criteria for Insomnia Disorder. In the DISCO trial (D efining the I mpact of improved S leep on CO gnitive function (DISCO)) participants will be randomised to digital automated CBT-I delivered by a web and/or mobile platform (in addition to treatment as usual (TAU)) or to a wait-list control (in addition to TAU). Online assessments will take place at 0 (baseline), 10 (post-treatment), and 24 (follow-up) weeks. At week 25, all participants allocated to the wait-list group will be offered digital CBT-I, at which point the controlled element of the trial will be complete. The primary outcome is self-reported cognitive impairment at post-treatment (10 weeks). Secondary outcomes include objective cognitive performance, insomnia severity, sleepiness, fatigue, and self-reported cognitive failures and emotional distress. All main analyses will be carried out on completion of follow-up assessments and will be based on the intention-to-treat principle. Further analyses will determine to what extent observed changes in self-reported cognitive impairment and objective cognitive performance are mediated by changes in sleep. The trial is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) based at Oxford University Hospitals NHS Trust and University of Oxford, and by the NIHR Oxford Health BRC.

Discussion: This study will be the first large-scale examination of the impact of digital CBT-I on self-reported cognitive impairment and objective cognitive performance.

Trial Registration: ISRCTN, ID: ISRCTN89237370 . Registered on 17 October 2016.
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http://dx.doi.org/10.1186/s13063-017-2012-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474001PMC
June 2017

Associations between Mobility, Cognition, and Brain Structure in Healthy Older Adults.

Front Aging Neurosci 2017 23;9:155. Epub 2017 May 23.

Oxford Centre for Functional MRI of the Brain, Nuffield Department of Clinical Neurosciences, University of OxfordJohn Radcliffe Hospital, Oxford, United Kingdom.

Mobility limitations lead to a cascade of adverse events in old age, yet the neural and cognitive correlates of mobility performance in older adults remain poorly understood. In a sample of 387 adults (mean age 69.0 ± 5.1 years), we tested the relationship between mobility measures, cognitive assessments, and MRI markers of brain structure. Mobility was assessed in 2007-2009, using gait, balance and chair-stands tests. In 2012-2015, cognitive testing assessed executive function, memory and processing-speed; gray matter volumes (GMV) were examined using voxel-based morphometry, and white matter microstructure was assessed using tract-based spatial statistics of fractional anisotropy, axial diffusivity (AD), and radial diffusivity (RD). All mobility measures were positively associated with processing-speed. Faster walking speed was also correlated with higher executive function, while memory was not associated with any mobility measure. Increased GMV within the cerebellum, basal ganglia, post-central gyrus, and superior parietal lobe was associated with better mobility. In addition, better performance on the chair-stands test was correlated with decreased RD and AD. Overall, our results indicate that, even in non-clinical populations, mobility measures can be sensitive to sub-clinical variance in cognition and brain structures.
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http://dx.doi.org/10.3389/fnagi.2017.00155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440513PMC
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

Sub-threshold depressive symptoms and brain structure: A magnetic resonance imaging study within the Whitehall II cohort.

J Affect Disord 2016 Nov 21;204:219-25. Epub 2016 Jun 21.

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

Background: Late-life sub-threshold depressive symptoms (i.e. depressive symptoms that do not meet the criteria for a diagnosis of major depressive disorder) are associated with impaired physical health and function, and increased risk of major depressive disorder. Magnetic resonance imaging (MRI) studies examining late-life major depressive disorder find structural brain changes in grey and white matter. However, the extent to which late-life sub-threshold depression is associated with similar hallmarks is not well established.

Methods: Participants with no history of major depressive disorder were selected from the Whitehall Imaging Sub-Study (n=358, mean age 69±5 years, 17% female). Depressive symptoms were measured using the Centre for Epidemiological Studies Depression Scale (CES-D) at three previous Whitehall II Study phases (2003-04, 2007-09 and 2012-13) and at the time of the MRI scan (2012-14). The relationships between current and cumulative depressive symptoms and MRI brain measures were explored using Voxel-Based Morphometry (VBM) for grey matter and Tract Based Spatial Statistics (TBSS) for white matter.

Results: Current sub-threshold depressive symptoms were associated with significant reductions in fractional anisotropy and increases in axial and radial diffusivity. There were no significant relationships between current depressive symptoms and grey matter measures, or cumulative depressive symptoms and MRI measures.

Limitations: The prevalence (10%) of sub-threshold depressive symptoms means that analyses may be underpowered to detect subtle differences in brain structure.

Conclusions: Current sub-threshold depressive symptoms are associated with changes in white matter microstructure, indicating that even mild depressive symptoms are associated with similar MRI hallmarks to those in major depressive disorder.
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http://dx.doi.org/10.1016/j.jad.2016.06.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5022868PMC
November 2016

A systematic review of MRI studies examining the relationship between physical fitness and activity and the white matter of the ageing brain.

Neuroimage 2016 05 16;131:81-90. Epub 2015 Oct 16.

FMRIB Centre, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, OX3 9DU, UK.

Higher levels of physical fitness or activity (PFA) have been shown to have beneficial effects on cognitive function and grey matter volumes in older adults. However, the relationship between PFA and the brain's white matter (WM) is not yet well established. Here, we aim to provide a comprehensive and systematic review of magnetic resonance imaging studies examining the effects of PFA on the WM of the ageing brain. Twenty-nine studies were included in the review: eleven examined WM volume, fourteen WM lesions, and nine WM microstructure. While many studies found that higher levels of PFA were associated with greater WM volumes, reduced volume or severity of WM lesions, or improved measures of WM microstructure, a number of negative findings have also been published. Meta-analyses of global measures of WM volume and WM lesion volume yielded significant, but small, effect sizes. Overall, we found evidence for cautious support of links between PFA and WM structure, and highlighted key areas for future research including the extent to which the relationship between PFA and WM structure is anatomically specific, the influence of possible confounding factors, and the relationship between PFA, WM and cognition.
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http://dx.doi.org/10.1016/j.neuroimage.2015.09.071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851455PMC
May 2016

Resilience and MRI correlates of cognitive impairment in community-dwelling elders.

Br J Psychiatry 2015 Nov 3;207(5):435-9. Epub 2015 Sep 3.

Anya Topiwala, BMBCh, Charlotte L. Allan, MBChB, Vyara Valkanova, MD, Enikő Zsoldos, MSc, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Nicola Filippini, DPhil, Claire E. Sexton, DPhil, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK and Oxford Centre for Functional MRI of the Brain (FMRIB), Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Abda Mahmood, MSc, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Archana Singh-Manoux, PhD, Department of Epidemiology and Public Health, UCL, London, UK and INSERM, U1018, Centre for Research in Epidemiology and Population Health, France; Clare E. Mackay, PhD, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Mika Kivimäki, PhD, Department of Epidemiology and Public Health, UCL, London, UK; Klaus P. Ebmeier, MD, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK

Background: The contribution of education and intelligence to resilience against age-related cognitive decline is not clear, particularly in the presence of 'normal for age' minor brain abnormalities.

Method: Participants (n = 208, mean age 69.2 years, s.d. = 5.4) in the Whitehall II imaging substudy attended for neuropsychological testing and multisequence 3T brain magnetic resonance imaging. Images were independently rated by three trained clinicians for global and hippocampal atrophy, periventricular and deep white matter changes.

Results: Although none of the participants qualified for a clinical diagnosis of dementia, a screen for cognitive impairment (Montreal Cognitive Assessment (MoCA) <26) was abnormal in 22%. Hippocampal atrophy, in contrast to other brain measures, was associated with a reduced MoCA score even after controlling for age, gender, socioeconomic status, years of education and premorbid IQ. Premorbid IQ and socioeconomic status were associated with resilience in the presence of hippocampal atrophy.

Conclusions: Independent contributions from a priori risk (age, hippocampal atrophy) and resilience (premorbid function, socioeconomic status) combine to predict measured cognitive impairment.
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http://dx.doi.org/10.1192/bjp.bp.114.152363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629074PMC
November 2015

Lifetime hypertension as a predictor of brain structure in older adults: cohort study with a 28-year follow-up.

Br J Psychiatry 2015 Apr 11;206(4):308-15. Epub 2014 Dec 11.

Charlotte L. Allan, MRCPsych, MD(Res), Enikõ Zsoldos, MSc, Nicola Filippini, DPhil, Claire E. Sexton, DPhil, Anya Topiwala, MRCPsych, Vyara Valkanova, MD, Neurobiology of Ageing Group, Department of Psychiatry, University of Oxford, Oxford, UK; Archana Singh-Manoux, PhD, Department of Epidemiology and Public Health, University College London, London, UK and INSERM U1018, Hôpital Paul Brousse, France; Adam G. Tabák, MD, PhD, Department of Epidemiology and Public Health, University College London, London, UK and 1st Department of Medicine, Semmelweis University Faculty of Medicine, Budapest, Hungary; Martin J. Shipley, MSc, Department of Epidemiology and Public Health, University College London, London, UK; Clare Mackay, PhD, Klaus P. Ebmeier, FRCPsych, MD, Neurobiology of Ageing Group, Department of Psychiatry, University of Oxford, Oxford, UK; Mika Kivimäki, PhD, Department of Epidemiology and Public Health, University College London, London, UK.

Background: Hypertension is associated with an increased risk of dementia and depression with uncertain longitudinal associations with brain structure.

Aims: To examine lifetime blood pressure as a predictor of brain structure in old age.

Method: A total of 190 participants (mean age 69.3 years) from the Whitehall II study were screened for hypertension six times (1985-2013). In 2012-2013, participants had a 3T-magnetic resonance imaging (MRI) brain scan. Data from the MRI were analysed using automated and visual measures of global atrophy, hippocampal atrophy and white matter hyperintensities.

Results: Longitudinally, higher mean arterial pressure predicted increased automated white matter hyperintensities (P<0.002). Cross-sectionally, hypertensive participants had increased automated white matter hyperintensities and visually rated deep white matter hyperintensities. There was no significant association with global or hippocampal atrophy.

Conclusions: Long-term exposure to high blood pressure predicts hyperintensities, particularly in deep white matter. The greatest changes are seen in those with severe forms of hypertension, suggesting a dose-response pattern.
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http://dx.doi.org/10.1192/bjp.bp.114.153536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381190PMC
April 2015

Accelerated changes in white matter microstructure during aging: a longitudinal diffusion tensor imaging study.

J Neurosci 2014 Nov;34(46):15425-36

Research Group for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, NO-0316 Oslo, Norway.

It is well established that human brain white matter structure changes with aging, but the timescale and spatial distribution of this change remain uncertain. Cross-sectional diffusion tensor imaging (DTI) studies indicate that, after a period of relative stability during adulthood, there is an accelerated decline in anisotropy and increase in diffusivity values during senescence; and, spatially, results have been discussed within the context of several anatomical frameworks. However, inferring trajectories of change from cross-sectional data can be challenging; and, as yet, there have been no longitudinal reports of the timescale and spatial distribution of age-related white matter change in healthy adults across the adult lifespan. In a longitudinal DTI study of 203 adults between 20 and 84 years of age, we used tract-based spatial statistics to characterize the pattern of annual change in fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity and examined whether there was an acceleration of change with age. We found extensive and overlapping significant annual decreases in fractional anisotropy, and increases in axial diffusivity, radial diffusivity, and mean diffusivity. Spatially, results were consistent with inferior-to-superior gradients of lesser-to-greater vulnerability. Annual change increased with age, particularly within superior regions, with age-related decline estimated to begin in the fifth decade. Charting white matter microstructural changes in healthy aging provides essential context to clinical studies, and future studies should compare age trajectories between healthy participants and at-risk populations and also explore the relationship between DTI rates of change and cognitive decline.
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http://dx.doi.org/10.1523/JNEUROSCI.0203-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4228140PMC
November 2014

Poor sleep quality is associated with increased cortical atrophy in community-dwelling adults.

Neurology 2014 Sep 3;83(11):967-73. Epub 2014 Sep 3.

From the University of Oxford (C.E.S., H.J.-B.), UK; and the University of Oslo (A.B.S., K.B.W., A.M.F.), Norway.

Objective: To examine the relationship between sleep quality and cortical and hippocampal volume and atrophy within a community-based sample, explore the influence of age on results, and assess the possible confounding effects of physical activity levels, body mass index (BMI), and blood pressure.

Methods: In 147 community-dwelling adults (92 female; age 53.9 ± 15.5 years), sleep quality was measured using the Pittsburgh Sleep Quality Index and correlated with cross-sectional measures of volume and longitudinal measures of atrophy derived from MRI scans separated by an average of 3.5 years. Exploratory post hoc analysis compared correlations between different age groups and included physical activity, BMI, and blood pressure as additional covariates.

Results: Poor sleep quality was associated with reduced volume within the right superior frontal cortex in cross-sectional analyses, and an increased rate of atrophy within widespread frontal, temporal, and parietal regions in longitudinal analyses. Results were largely driven by correlations within adults over the age of 60, and could not be explained by variation in physical activity, BMI, or blood pressure. Sleep quality was not associated with hippocampal volume or atrophy.

Conclusions: We found that longitudinal measures of cortical atrophy were widely correlated with sleep quality. Poor sleep quality may be a cause or a consequence of brain atrophy, and future studies examining the effect of interventions that improve sleep quality on rates of atrophy may hold key insights into the direction of this relationship.
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http://dx.doi.org/10.1212/WNL.0000000000000774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162301PMC
September 2014
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