Abda Mahmood

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

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.

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

ABSTRACT 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. HIGHLIGHTSClassification criteria for periventricular/deep white matter hyperintensities are compared.The definition of PWMH and DWMH is not a major obstacle for study comparison.PWMH and DWMH have different functional, microstructural and clinical correlates.10 mm distance rule gave best separation in terms of associations with the tested factors.

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

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.

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

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.

A nested mechanistic sub-study into the effect of tranexamic acid versus placebo on intracranial haemorrhage and cerebral ischaemia in isolated traumatic brain injury: study protocol for a randomised controlled trial (CRASH-3 Trial Intracranial Bleeding Mechanistic Sub-Study [CRASH-3 IBMS])

BackgroundTranexamic acid prevents blood clots from breaking down and reduces bleeding. However, it is uncertain whether tranexamic acid is effective in traumatic brain injury. The CRASH-3 trial is a randomised controlled trial that will examine the effect of tranexamic acid (versus placebo) on death and disability in 13,000 patients with traumatic brain injury. The CRASH-3 trial hypothesizes that tranexamic acid will reduce intracranial haemorrhage, which will reduce the risk of death. Although it is possible that tranexamic acid will reduce intracranial bleeding, there is also a potential for harm. In particular, tranexamic acid may increase the risk of cerebral thrombosis and ischaemia. The protocol detailed here is for a mechanistic sub-study nested within the CRASH-3 trial. This mechanistic sub-study aims to examine the effect of tranexamic acid (versus placebo) on intracranial bleeding and cerebral ischaemia.MethodsThe CRASH-3 Intracranial Bleeding Mechanistic Sub-Study (CRASH-3 IBMS) is nested within a prospective, double-blind, multi-centre, parallel-arm randomised trial called the CRASH-3 trial. The CRASH-3 IBMS will be conducted in a cohort of approximately 1000 isolated traumatic brain injury patients enrolled in the CRASH-3 trial. In the CRASH-3 IBMS, brain scans acquired before and after randomisation are examined, using validated methods, for evidence of intracranial bleeding and cerebral ischaemia. The primary outcome is the total volume of intracranial bleeding measured on computed tomography after randomisation, adjusting for baseline bleeding volume. Secondary outcomes include progression of intracranial haemorrhage (from pre- to post-randomisation scans), new intracranial haemorrhage (seen on post- but not pre-randomisation scans), intracranial haemorrhage following neurosurgery, and new focal ischaemic lesions (seen on post-but not pre-randomisation scans). A linear regression model will examine whether receipt of the trial treatment can predict haemorrhage volume. Bleeding volumes and new ischaemic lesions will be compared across treatment groups using relative risks and 95% confidence intervals.DiscussionThe CRASH-3 IBMS will provide an insight into the mechanism of action of tranexamic acid in traumatic brain injury, as well as information about the risks and benefits. Evidence from this trial could inform the management of patients with traumatic brain injury.Trial registrationThe CRASH-3 trial was prospectively registered and the CRASH-3 IBMS is an addition to the original protocol registered at the International Standard Randomised Controlled Trials registry (ISRCTN15088122) 19 July 2011, and ClinicalTrials.gov on 25 July 2011 (NCT01402882).

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

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.

Occupational stress, bullying and resilience in old age.

Our working years increasingly extend into the late 60s and may soon include the 70s for some people. Thus the question whether work stress has a cumulative effect in older age, and whether older employees are more vulnerable to certain sources of work stress, such as bullying in the work place, is becoming increasingly relevant. We review some of the mechanisms, which translate cumulative stress at work into ill health, particularly in older age, and summarise what is known about the effect of age-specific stress, taking age-related bullying as an example.

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

Abstract Episodic and spatial memory are commonly impaired in ageing and Alzheimers 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. HighlightsEpisodic and visuospatial memory engaged a common medial temporal lobe substrate at rest.However, the resting‐state functional connections of the MTL differed based on the memory demand.Visuospatial memory was associated with hippocampal‐parietal and motorparietal interaction.Verbal memory was associated with hippocampus‐frontal pole anticorrelation.Findings provide novel insights into resting‐state brain‐behaviour interactions in older adults.

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

ABSTRACT Proton magnetic resonance spectroscopy (1H‐MRS) has provided valuable information about the neurochemical profile of Alzheimers 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) &egr;4, an established risk gene for AD. We quantified metabolites within an 8 cm3 voxel within the posterior cingulate cortex (PCC)/precuneus in 30 younger (20–40 years) and 151 cognitively healthy older individuals (60–85 years). All 1H‐MRS scans were performed at 3 T 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 1H‐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.

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

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.