Study protocol: the Whitehall II imaging sub-study

Filippini, Nicola; Zsoldos, Enikő; Haapakoski, Rita; Sexton, Claire E.; Mahmood, Abda; Allan, Charlotte L.; Topiwala, Anya; Valkanova, Vyara; Brunner, Eric J.; Shipley, Martin J.; Auerbach, Edward J.; Moeller, Steen; Uğurbil, Kâmil; Xu, Junqian; Yacoub, Essa; Andersson, Jesper; Bijsterbosch, Janine; Clare, Stuart; Griffanti, Ludovica; Hess, Aaron T.; Jenkinson, Mark; Miller, Karla L.; Salimi‐Khorshidi, Gholamreza; Sotiropoulos, Stamatios N.; Voets, Natalie L.; Smith, Stephen M.; Geddes, John; Singh‐Manoux, Archana; Mackay, Clare E.; Kivimäki, Mika; Ebmeier, Klaus P.

doi:10.1186/1471-244x-14-159

Cited by 91 publications

(150 citation statements)

References 105 publications

(112 reference statements)

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“…We used T1-weighted and diffusion tensor (DTI) 3T MRI sequences for these analyses. 30 Full technical details are in the appendix. In brief, we initially examined associations between alcohol use and grey matter using voxel based morphometry, an objective method to compare grey matter density between individuals in each voxel (smallest distinguishable image volume) of the structural image.…”

Section: Mri Analysismentioning

confidence: 99%

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

Topiwala

Allan

Valkanova

et al. 2017

BMJ

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341

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Objectives To investigate whether moderate alcohol consumption has a favourable or adverse association or no association with brain structure and function. Design 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). Setting Community dwelling adults enrolled in the Whitehall II cohort based in the UK (the Whitehall II imaging substudy). Participants 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. Main outcome measures 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. Results 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. Conclusions 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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Section: Mri Analysismentioning

confidence: 99%

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

Topiwala

Allan

Valkanova

et al. 2017

BMJ

Self Cite

341

280

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“…Forty-eight participants were selected from subjects recruited to the Whitehall II imaging sub-study between May 2012 and December 2014 [19]. All participants were members of the Whitehall II study, a prospective occupation cohort study established in 1985 [20].…”

Section: Participantsmentioning

confidence: 99%

“…Ethical approval was obtained from the University of Oxford Central University Research Ethics Committee, and the University College London Medical School Committee on the Ethics of Human Research. Informed written consent was obtained from all participants [19].…”

Section: Participantsmentioning

confidence: 99%

“…The detailed study protocol has been previously published elsewhere [19]. We assessed cognitive impairment using the Montreal Cognitive Assessment (MoCA) [21], and studied 24 cognitively impaired participants (MoCA <26), who would qualify for a clinical diagnosis of mild cognitive impairment (MCI), alongside 24 age and gender matched cognitively normal participants (MoCA >26), who were free from other comorbidities such as depression (Supplementary Table 1).…”

Section: Participantsmentioning

confidence: 99%

“…As such, brain imaging changes are useful surrogate markers of brain health and aging. Here, we investigated the potential utility of DNAm profiling as a peripheral marker for cognitive decline and brain health in the Whitehall II imaging sub-study [19], which provides a valuable source of longitudinal data to explore factors hypothesized to affect brain health and cognitive aging.…”

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confidence: 99%

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Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

et al. 2018

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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. DNA methylation (DNAm) changes have been linked with the pathophysiology of brain aging, Alzheimer's disease (AD) and other types of dementia [1,2]. Considering the relative stability of DNAm and the fact that it is directly modulated by both underlying genetic sequence and environmental exposures it appears as a promising peripheral biomarker for brain-related changes [3]. Peripheral changes in mRNA and proteins that are downstream of DNAm regulation further support this concept [4,5]. Studies have shown differences in blood DNAm when comparing AD subjects with controls [6], but interestingly when looking at specific genes there is little overlap between brain and blood DNAm changes in AD [7,8]. However, a good peripheral biomarker does not have to mirror disease-associated changes in the brain; it could also simply represent a peripheral response to central pathology. At present, there is limited data available on the potential utility of peripheral DNAm as a marker for cognitive decline before the onset of dementia. One study of patients with Type 2 diabetes mellitus who later developed presymptomatic dementia highlighted leukocyte DNAm changes that were comparable to changes identified in blood in AD patients and could thus potentially represent early markers of dementia [9]. Recently DNAm epigenetic clocks have been developed, which provide a measure of epigenetic age, based on DNAm levels at 353 CpG sites [10] and 71 CpG sites [11], respectively. A number of studies have utilized the epigenetic age in blood, based on the DNAm epigenetic clock, to show correlations with cognitive function, white matter hyperintensities (WMH), Parkinson's disease, Down syndrome and all-cause mortality [12][13][14][15][16].

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Association of Midlife Cardiovascular Risk Profiles With Cerebral Perfusion at Older Ages

et al. 2019

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Key Points Question Is midlife cardiovascular risk associated with cerebral blood flow in older age, and does this association vary with age? Findings In this longitudinal cohort study of 116 older adults without dementia, higher cardiovascular risk scores during a 20-year period were significantly associated with lower cerebral blood flow to the medial temporal, parietal, and occipital cortices. The association varied during the life span such that cardiovascular risk in midlife but not in later life was significantly associated with cerebral hypoperfusion in older age. Meaning Because cerebral hypoperfusion is an early mechanism in Alzheimer disease and vascular dementia, these findings may inform the development of dementia prevention strategies aimed at managing cardiovascular health.

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Study protocol: the Whitehall II imaging sub-study

Cited by 91 publications

References 105 publications

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

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

Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

Association of Midlife Cardiovascular Risk Profiles With Cerebral Perfusion at Older Ages

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