Validation of the brain health index in the European Prevention of Alzheimer's Dementia cohort.

Background: Brain Health Index (BHI) assimilates various MRI sequences, giving a quantitative measure of brain health. To date, BHI validation has been cross-sectional and limited to selected populations. Further large-scale validation and assessment of temporal change is required to understand its clinical utility. Aim: Assess 1) relationships between variables associated with cognitive decline and BHI 2) associations between BHI and measures of cognition and 3) longitudinal changes in BHI and relationship with cognitive function. Methods: BHI computation involved Gaussian mixture-model cluster analysis of T1, T2, T2*, and T2 FLAIR MRI data from participants within the European Prevention of Alzheimer's Dementia (EPAD) cohort. Group differences (gender- and health-based) were evaluated using independent samples Welch's t-tests. Relationships between BHI, age and cognitive tests used linear regression. Longitudinal analysis (12/24 months) utilised mixed linear regression models to examine BHI changes, and paired BHI/cognition associations. Results: Data from N = 1496 predominantly Caucasian participants (50-88 years old, 43.32% male) were used. BHI scores were lower in those with diabetes (p < 0.001, d = 0.419), hypertension (p < 0.001, d = 0.375), hypercholesterolemia (p < 0.001, d = 0.193) and stroke (p < 0.05, d = 0.512). APOE was not significantly related to BHI scores. After correction for age, cross-sectional BHI scores were significantly associated with all measures of cognitive function in males, but only the Four Mountains Test (4MT) in females. Longitudinal change in BHI and cognition were not consistently related. Conclusions: BHI is a valid marker of cognitive decline and relatively stable over 1-2 year follow-up periods. Further work should assess temporal changes over a longer duration and determine relationships between BHI and cognition in more diverse populations.

Allopurinol and blood pressure variability following ischemic stroke and transient ischemic attack: a secondary analysis of XILO-FIST.

Blood Pressure Variability (BPV) is associated with cardiovascular risk and serum uric acid level. We investigated whether BPV was lowered by allopurinol and whether it was related to neuroimaging markers of cerebral small vessel disease (CSVD) and cognition. We used data from a randomised, double-blind, placebo-controlled trial of two years allopurinol treatment after recent ischemic stroke or transient ischemic attack. Visit-to-visit BPV was assessed using brachial blood pressure (BP) recordings. Short-term BPV was assessed using ambulatory BP monitoring (ABPM) performed at 4 weeks and 2 years. Brain MRI was performed at baseline and 2 years. BPV measures were compared between the allopurinol and placebo groups, and with CSVD and cognition. 409 participants (205 allopurinol; 204 placebo) were included in the visit-to-visit BPV analyses. There were no significant differences found between placebo and allopurinol groups for any measure of visit-to-visit BPV. 196 participants were included in analyses of short-term BPV at week 4. Two measures were reduced by allopurinol: the standard deviation (SD) of systolic BP (by 1.30 mmHg (95% confidence interval (CI) 0.18-2.42, p = 0.023)); and the average real variability (ARV) of systolic BP (by 1.31 mmHg (95% CI 0.31-2.32, p = 0.011)). There were no differences in other measures at week 4 or in any measure at 2 years, and BPV was not associated with CSVD or cognition. Allopurinol treatment did not affect visit-to-visit BPV in people with recent ischemic stroke or TIA. Two BPV measures were reduced at week 4 by allopurinol but not at 2 years.

Vagus Nerve Stimulation Paired With Mobility Training in Chronic Ischemic Stroke: A Case Report.

OBJECTIVE: The purpose of this case report is to describe pairing vagus nerve stimulation (VNS) with mobility training in an individual after stroke. METHODS: A 53-year-old man with left hemiparesis 14.2 months after an ischemic stroke participated in a pilot study investigating the safety and feasibility of VNS paired with upper limb rehabilitation. In addition to upper limb impairment, the participant had impaired gait and wanted to improve his mobility. A single-subject design investigation of VNS paired with self-directed mobility training was conducted. Following the conclusion of the pilot study, the participant was instructed to complete daily sessions of self-activated VNS paired with walking or stationary biking. The 10-Meter Walk Test and timed distance (6-Minute Walk Test) were assessed at 4 baseline points and at 3 to 41 months after mobility training. RESULTS: The participant had stable baseline values and was classified as a household ambulator with a quad cane. After VNS-paired mobility training, statistically significant improvements were observed in all measures, with the greatest improvements at 9 months exceeding the minimal detectable change: self-selected gait speed from 0.34 (standard deviation [SD] = 0.01) to 0.60 meters/second, fast gait speed from 0.37 (SD = 0.03) to 0.79 meters/second, and 6-Minute Walk Test distance from 106.91 (SD = 6.38) to 179.83 meters. The participant reported increased confidence and balance when walking. No falls or adverse events were reported. CONCLUSION: The participant demonstrated improved gait speed and timed distance after VNS-paired mobility training. Randomized, blinded trials are needed to determine treatment efficacy. IMPACT: This is the first documented case of VNS-paired mobility training in an individual with chronic poststroke gait impairments. VNS paired with mobility training may improve poststroke gait impairments.

Sleep quality, perivascular spaces and brain health markers in ageing - A longitudinal study in the Lothian Birth Cohort 1936.

BACKGROUND: Sleep is thought to play a major role in brain health and general wellbeing. However, few longitudinal studies have explored the relationship between sleep habits and imaging markers of brain health, particularly markers of brain waste clearance such as perivascular spaces (PVS), of neurodegeneration such as brain atrophy, and of vascular disease, such as white matter hyperintensities (WMH). We explore these associations using data collected over 6 years from a birth cohort of older community-dwelling adults in their 70s. METHOD: We analysed brain MRI data from ages 73, 76 and 79 years, and self-reported sleep duration, sleep quality and vascular risk factors from community-dwelling participants in the Lothian Birth Cohort 1936 (LBC1936) study. We calculated sleep efficiency (at age 76), quantified PVS burden (at age 73), and WMH and brain volumes (age 73 to 79), calculated the white matter damage metric, and used structural equation modelling (SEM) to explore associations and potential causative pathways between indicators related to brain waste cleaning (i.e., sleep and PVS burden), brain and WMH volume changes during the 8th decade of life. RESULTS: Lower sleep efficiency was associated with a reduction in normal-appearing white matter (NAWM) volume (ß = 0.204, P = 0.009) from ages 73 to 79, but not concurrent volume (i.e. age 76). Increased daytime sleep correlated with less night-time sleep (r = -0.20, P < 0.001), and with increasing white matter damage metric (ß = -0.122, P = 0.018) and faster WMH growth (ß = 0.116, P = 0.026). Shorter night-time sleep duration was associated with steeper 6-year reduction of NAWM volumes (ß = 0.160, P = 0.011). High burden of PVS at age 73 (volume, count, and visual scores), was associated with faster deterioration in white matter: reduction of NAWM volume (ß = -0.16, P = 0.012) and increasing white matter damage metric (ß = 0.37, P < 0.001) between ages 73 and 79. On SEM, centrum semiovale PVS burden mediated 5% of the associations between sleep parameters and brain changes. CONCLUSION: Sleep impairments, and higher PVS burden, a marker of impaired waste clearance, were associated with faster loss of healthy white matter and increasing WMH in the 8th decade of life. A small percentage of the effect of sleep in white matter health was mediated by the burden of PVS consistent with the proposed role for sleep in brain waste clearance.

Xanthine oxidase inhibition and white matter hyperintensity progression following ischaemic stroke and transient ischaemic attack (XILO-FIST): a multicentre, double-blinded, randomised, placebo-controlled trial.

Background: People who experience an ischaemic stroke are at risk of recurrent vascular events, progression of cerebrovascular disease, and cognitive decline. We assessed whether allopurinol, a xanthine oxidase inhibitor, reduced white matter hyperintensity (WMH) progression and blood pressure (BP) following ischaemic stroke or transient ischaemic attack (TIA). Methods: In this multicentre, prospective, randomised, double-blinded, placebo-controlled trial conducted in 22 stroke units in the United Kingdom, we randomly assigned participants within 30-days of ischaemic stroke or TIA to receive oral allopurinol 300 mg twice daily or placebo for 104 weeks. All participants had brain MRI performed at baseline and week 104 and ambulatory blood pressure monitoring at baseline, week 4 and week 104. The primary outcome was the WMH Rotterdam Progression Score (RPS) at week 104. Analyses were by intention to treat. Participants who received at least one dose of allopurinol or placebo were included in the safety analysis. This trial is registered with ClinicalTrials.gov, NCT02122718. Findings: Between 25th May 2015 and the 29th November 2018, 464 participants were enrolled (232 per group). A total of 372 (189 with placebo and 183 with allopurinol) attended for week 104 MRI and were included in analysis of the primary outcome. The RPS at week 104 was 1.3 (SD 1.8) with allopurinol and 1.5 (SD 1.9) with placebo (between group difference -0.17, 95% CI -0.52 to 0.17, p = 0.33). Serious adverse events were reported in 73 (32%) participants with allopurinol and in 64 (28%) with placebo. There was one potentially treatment related death in the allopurinol group. Interpretation: Allopurinol use did not reduce WMH progression in people with recent ischaemic stroke or TIA and is unlikely to reduce the risk of stroke in unselected people. Funding: The British Heart Foundation and the UK Stroke Association.

Contribution of white matter hyperintensities to ventricular enlargement in older adults.

Lateral ventricles might increase due to generalized tissue loss related to brain atrophy. Alternatively, they may expand into areas of tissue loss related to white matter hyperintensities (WMH). We assessed longitudinal associations between lateral ventricle and WMH volumes, accounting for total brain volume, blood pressure, history of stroke, cardiovascular disease, diabetes and smoking at ages 73, 76 and 79, in participants from the Lothian Birth Cohort 1936, including MRI data from all available time points. Lateral ventricle volume increased steadily with age, WMH volume change was more variable. WMH volume decreased in 20% and increased in remaining subjects. Over 6 years, lateral ventricle volume increased by 3% per year of age, 0.1% per mm Hg increase in blood pressure, 3.2% per 1% decrease of total brain volume, and 4.5% per 1% increase of WMH volume. Over time, lateral ventricle volumes were 19% smaller in women than men. Ventricular and WMH volume changes are modestly associated and independent of general brain atrophy, suggesting that their underlying processes do not fully overlap.

Intracranial hemodynamic relationships in patients with cerebral small vessel disease.

OBJECTIVE: To investigate cerebrovascular reactivity (CVR), blood flow, vascular and CSF pulsatility, and their independent relationship with cerebral small vessel disease (SVD) features in patients with minor ischemic stroke and MRI evidence of SVD. METHODS: We recruited patients with minor ischemic stroke and assessed CVR using blood oxygen level-dependent MRI during a hypercapnic challenge, cerebral blood flow (CBF), vascular and CSF pulsatility using phase-contrast MRI, and structural magnetic resonance brain imaging to quantify white matter hyperintensities (WMHs) and perivascular spaces (PVSs). We used multiple regression to identify parameters associated with SVD features, controlling for patient characteristics. RESULTS: Fifty-three of 60 patients completed the study with a full data set (age 68.0% ± 8.8 years, 74% male, 75% hypertensive). After controlling for age, sex, and systolic blood pressure, lower white matter CVR was associated with higher WMH volume (-0.01%/mm Hg per log10 increase in WMH volume, p = 0.02), basal ganglia PVS (-0.01%/mm Hg per point increase in the PVS score, p = 0.02), and higher venous pulsatility (superior sagittal sinus -0.03%/mm Hg, p = 0.02, per unit increase in the pulsatility index) but not with CBF (p = 0.58). Lower foramen magnum CSF stroke volume was associated with worse white matter CVR (0.04%/mm Hg per mL increase in stroke volume, p = 0.04) and more severe basal ganglia PVS (p = 0.09). CONCLUSIONS: Lower CVR, higher venous pulsatility, and lower foramen magnum CSF stroke volume indicate that dynamic vascular dysfunctions underpin PVS dysfunction and WMH development. Further exploration of microvascular dysfunction and CSF dynamics may uncover new mechanisms and intervention targets to reduce SVD lesion development, cognitive decline, and stroke.

Cortical thickness, white matter hyperintensities, and cognition after stroke.

BACKGROUND: A thinner cerebral cortex is associated with higher white matter hyperintensity burden and cognitive impairment in community-dwelling and dementia cohorts. It is important to assess these associations in people with ischemic stroke because their cerebrovascular disease profiles are different to these cohorts. AIMS: We aimed to determine whether cortical thickness was related to white matter hyperintensity burden and cognition after ischemic stroke. METHODS: We measured cortical thickness using advanced normalization tools' "KellyKapowski" function in 244 patients with ischemic stroke or transient ischemic attack from the Virtual International Stroke Trials Archive. We measured white matter hyperintensity burden via quantitative volumes and Fazekas score. We extracted data on vascular risk factors at baseline and Mini Mental State Examination scores at one year. We assessed associations between imaging and clinical data using correlation and multiple linear regression. RESULTS: Pairwise correlation showed that higher white matter hyperintensity Fazekas score was associated with a thinner cortex (rho = -0.284, P < 0.0001). White matter hyperintensities were generally distributed adjacent to and above the lateral ventricles. Voxel-wise analyses showed statistically significant negative associations between cortical thickness and white matter hyperintensities across fronto-temporal and inferior parietal cortical regions. Mean cortical thickness was positively related to Mini Mental State Examination in pair-wise correlation (r = 0.167, P = 0.0088) but there was no independent association after adjustment for age and white matter hyperintensities (beta = 0.016, P = 0.7874). CONCLUSIONS: Cortical thickness was not an independent predictor of cognition after ischemic stroke. Further work is required to understand how white matter hyperintensities are associated with a thinner cortex in temporal regions but less so in more superior regions where white matter hyperintensities are generally found in people with stroke.

An Exploratory Study of Predictors of Response to Vagus Nerve Stimulation Paired with Upper-Limb Rehabilitation After Ischemic Stroke.

We have previously shown the safety and feasibility of vagus nerve stimulation (VNS) paired with upper-limb rehabilitation after ischemic stroke. In this exploratory study, we assessed whether clinical and brain MRI variables predict response to treatment. We used data from two completed randomised and blinded clinical trials (N = 35). All participants had moderate to severe upper-limb weakness and were randomised to 6-weeks intensive physiotherapy with or without VNS. Participants had 3 T brain MRI at baseline. The primary outcome was change in Fugl-Meyer Assessment, upper-extremity score (FMA-UE) from baseline to the first day after therapy completion. We used general linear regression to identify clinical and brain MRI predictors of change in FMA-UE. VNS-treated participants had greater improvement in FMA-UE at day-1 post therapy than controls (8.63 ± 5.02 versus 3.79 ± 5.04 points, t = 2.83, Cohen's d = 0.96, P = 0.008). Higher cerebrospinal fluid volume was associated with less improvement in FMA-UE in the control but not VNS group. This was also true for white matter hyperintensity volume but not after removal of an outlying participant from the control group. Responders in the VNS group had more severe arm impairment at baseline than responders to control. A phase III trial is now underway to formally determine whether VNS improves outcomes and will explore whether these differ in people with more severe baseline upper-limb disability and cerebrovascular disease.

Combining Neurovascular and Neurodegenerative Magnetic Resonance Imaging Measures in Stroke.

Background and Purpose- Individual markers of cerebral small vessel disease and cerebral atrophy explain a small proportion of variance in vascular risk factors and cognitive function. Combining these markers into a single measure of neurovascular and neurodegenerative disease may be more powerful. We assessed this using data contained in the Virtual International Stroke Trials Archive - Prevention sub-archive. Methods- We extracted white matter hyperintensities (WMH) and cerebrospinal fluid (CSF) volumes from 317 people with ischemic stroke or transient ischemic attack who had baseline magnetic resonance imaging. We assessed progression of volumes in 208 people who had 2-year follow-up magnetic resonance imaging. WMH and CSF volumes were segmented from fluid attenuated inversion recovery and T1 images. The combined neurovascular and neurodegenerative measure was the sum of WMH and CSF volume normalized by intracranial volume. We assessed (1) the relationship between baseline vascular risk factors and imaging markers; and (2) the relationship between baseline imaging markers and Mini-Mental State Examination score at follow-up using multiple linear regression. We also assessed implications for sample size calculations using n=208 participants with follow-up magnetic resonance imaging. Results- Vascular risk factors accounted for 7%, 11%, and 12% of the variance in WMH, CSF, and combined volume, respectively (all P<0.001). The association between baseline combined volume and 6-month follow-up Mini-Mental State Examination (ß=-0.442; SE, 0.07; P<0.0001) was 32% greater than WMH (ß=-0.302; SE, 0.06; P<0.0001) and 12% greater than CSF (ß=-0.391; SE, 0.07; P<0.0001) alone. The combined volume required between 207 and 3305 (20%) fewer patients per arm than WMH alone to detect reductions of 10% to 40% in volume progression over 2 years. Conclusions- A combined neurovascular and neurodegenerative magnetic resonance imaging measure including WMH and CSF volume was more closely related to vascular risk factors and cognitive function than either WMH or CSF volume alone. The combined volume may be a more sensitive measurement for clinical trials.

Stroke aetiological classification reliability and effect on trial sample size: systematic review, meta-analysis and statistical modelling.

BACKGROUND: Inter-observer variability in stroke aetiological classification may have an effect on trial power and estimation of treatment effect. We modelled the effect of misclassification on required sample size in a hypothetical cardioembolic (CE) stroke trial. METHODS: We performed a systematic review to quantify the reliability (inter-observer variability) of various stroke aetiological classification systems. We then modelled the effect of this misclassification in a hypothetical trial of anticoagulant in CE stroke contaminated by patients with non-cardioembolic (non-CE) stroke aetiology. Rates of misclassification were based on the summary reliability estimates from our systematic review. We randomly sampled data from previous acute trials in CE and non-CE participants, using the Virtual International Stroke Trials Archive. We used bootstrapping to model the effect of varying misclassification rates on sample size required to detect a between-group treatment effect across 5000 permutations. We described outcomes in terms of survival and stroke recurrence censored at 90 days. RESULTS: From 4655 titles, we found 14 articles describing three stroke classification systems. The inter-observer reliability of the classification systems varied from 'fair' to 'very good' and suggested misclassification rates of 5% and 20% for our modelling. The hypothetical trial, with 80% power and alpha 0.05, was able to show a difference in survival between anticoagulant and antiplatelet in CE with a sample size of 198 in both trial arms. Contamination of both arms with 5% misclassified participants inflated the required sample size to 237 and with 20% misclassification inflated the required sample size to 352, for equivalent trial power. For an outcome of stroke recurrence using the same data, base-case estimated sample size for 80% power and alpha 0.05 was n = 502 in each arm, increasing to 605 at 5% contamination and 973 at 20% contamination. CONCLUSIONS: Stroke aetiological classification systems suffer from inter-observer variability, and the resulting misclassification may limit trial power. TRIAL REGISTRATION: Protocol available at reviewregistry540 .

Investigating the Relationship between Cerebral Blood Flow and Cognitive Function in Hemodialysis Patients.

BACKGROUND: The immediate and longer-term effects of hemodialysis on cerebral circulation, cerebral structure, and cognitive function are poorly understood. METHODS: In a prospective observational cohort study of 97 adults (median age 59 years) receiving chronic hemodialysis, we used transcranial Doppler ultrasound to measure cerebral arterial mean flow velocity (MFV) throughout dialysis. Using a well validated neuropsychological protocol, we assessed cognitive function during and off dialysis and after 12 months of treatment. We also used brain magnetic resonance imaging (MRI) to assess atrophy, white matter hyperintensities (WMHs), and diffusion parameters, and tested correlations between MFV, cognitive scores, and changes on MRI. RESULTS: MFV declined significantly during dialysis, correlating with ultrafiltrate volumes. Percentage of decline in MFV correlated with intradialytic decline in cognitive function, including global function, executive function, and verbal fluency. At follow-up, 73 patients were available for repeat testing, 34 of whom underwent repeat MRI. In a subgroup of patients followed for 12 months of continued dialysis, percentage of decline in MFV correlated significantly with lower global and executive function and with progression of WMH burden (a marker of small vessel disease). Twelve of 15 patients who received renal transplants during follow-up had both early and follow-up off-dialysis assessments. After transplant, patients' memory (on a delayed recall test) improved significantly; increased fractional anisotropy of white matter (a measure of cerebral diffusion) in these patients correlated with improving executive function. CONCLUSIONS: Patients undergoing hemodialysis experience transient decline in cerebral blood flow, correlating with intradialytic cognitive dysfunction. Progressive cerebrovascular disease occurred in those continuing dialysis, but not in transplanted patients. Cognitive function and cerebral diffusion improved after transplant.

Study protocol for a pivotal randomised study assessing vagus nerve stimulation during rehabilitation for improved upper limb motor function after stroke.

BACKGROUND: Vagus nerve stimulation (VNS) paired with a motor task improves motor outcome in rat stroke models. It is hypothesised that VNS delivered during rehabilitation will improve upper limb function compared to control rehabilitation therapy. Two pilot clinical studies demonstrated acceptable safety and feasibility of VNS paired with rehabilitation for improved upper limb function after stroke. Participants who received rehabilitation paired with VNS demonstrated clinically meaningful improvements in motor function that exceed gains seen among controls who received similar rehabilitation without VNS. These preliminary data support a larger pivotal trial. METHODS: VNS-REHAB (VNS-Rehabilitation) is a pivotal, multi-site, double-blinded, randomised trial designed to evaluate safety and efficacy of VNS paired with upper limb rehabilitation after ischaemic stroke. The study will include up to 120 participants with upper limb weakness due to stroke nine months to 10 years prior. All participants will be implanted with a VNS device and randomised to receive either Active (0.8 mA) or Control VNS (0.0 mA) paired with upper limb rehabilitation. All participants receive 18 sessions of in-clinic therapy for six weeks, followed by a home-based therapy for three months. The rehabilitation therapy involves progressive, functionally based and intensive practice of hand and arm tasks. VNS is delivered during each movement repetition. After blinded follow-up is completed, the Active vagus nerve stimulation group continues with home-based Active VNS and the Control group receive six weeks of in-clinic therapy with Active VNS followed by home-based Active VNS. The primary efficacy endpoint will be the difference in Fugl-Meyer assessment-upper extremity scores between the Active VNS and Control VNS groups at the end of six weeks of in-clinic therapy. Additional secondary endpoints will also be measured. Safety will be assessed with analysis of adverse events and device complications during study participation. DISCUSSION: This pivotal trial will determine whether VNS paired with rehabilitation is a safe and effective treatment for improving arm function after stroke.Trial Registration: ClinicalTrials.gov, NCT03131960. Registered on 27 April 2017.

The Whole Picture: From Isolated to Global MRI Measures of Neurovascular and Neurodegenerative Disease.

Structural magnetic resonance imaging (MRI) has been used to characterise the appearance of the brain in cerebral small vessel disease (SVD), ischaemic stroke, cognitive impairment, and dementia. SVD is a major cause of stroke and dementia; features of SVD include white matter hyperintensities (WMH) of presumed vascular origin, lacunes of presumed vascular origin, microbleeds, and perivascular spaces. Cognitive impairment and dementia have traditionally been stratified into subtypes of varying origin, e.g., vascular dementia versus dementia of the Alzheimer's type (Alzheimer's disease; AD). Vascular dementia is caused by reduced blood flow in the brain, often as a result of SVD, and AD is thought to have its genesis in the accumulation of tau and amyloid-beta leading to brain atrophy. But after early seminal studies in the 1990s found neurovascular disease features in around 30% of AD patients, it is becoming recognised that so-called "mixed pathologies" (of vascular and neurodegenerative origin) exist in many more patients diagnosed with stroke, only one type of dementia, or cognitive impairment. On the back of these discoveries, attempts have recently been made to quantify the full extent of degenerative and vascular disease in the brain in vivo on MRI. The hope being that these "global" methods may one day lead to better diagnoses of disease and provide more sensitive measurements to detect treatment effects in clinical trials. Indeed, the "Total MRI burden of cerebral small vessel disease", the "Brain Health Index" (BHI), and "MRI measure of degenerative and cerebrovascular pathology in Alzheimer disease" have all been shown to have stronger associations with clinical and cognitive phenotypes than individual brain MRI features. This chapter will review individual structural brain MRI features commonly seen in SVD, stroke, and dementia. The relationship between these features and differing clinical and cognitive phenotypes will be discussed along with developments in their measurement and quantification. The chapter will go on to review emerging methods for quantifying the collective burden of structural brain MRI findings and how these "whole picture" methods may lead to better diagnoses of neurovascular and neurodegenerative disorders.

Longitudinal serum S100ß and brain aging in the Lothian Birth Cohort 1936.

Elevated serum and cerebrospinal fluid concentrations of S100ß, a protein predominantly found in glia, are associated with intracranial injury and neurodegeneration, although concentrations are also influenced by several other factors. The longitudinal association between serum S100ß concentrations and brain health in nonpathological aging is unknown. In a large group (baseline N = 593; longitudinal N = 414) of community-dwelling older adults at ages 73 and 76 years, we examined cross-sectional and parallel longitudinal changes between serum S100ß and brain MRI parameters: white matter hyperintensities, perivascular space visibility, white matter fractional anisotropy and mean diffusivity (MD), global atrophy, and gray matter volume. Using bivariate change score structural equation models, correcting for age, sex, diabetes, and hypertension, higher S100ß was cross-sectionally associated with poorer general fractional anisotropy (r = -0.150, p = 0.001), which was strongest in the anterior thalamic (r = -0.155, p < 0.001) and cingulum bundles (r = -0.111, p = 0.005), and survived false discovery rate correction. Longitudinally, there were no significant associations between changes in brain imaging parameters and S100ß after false discovery rate correction. These data provide some weak evidence that S100ß may be an informative biomarker of brain white matter aging.

The brain health index: Towards a combined measure of neurovascular and neurodegenerative structural brain injury.

Background A structural magnetic resonance imaging measure of combined neurovascular and neurodegenerative burden may be useful as these features often coexist in older people, stroke and dementia. Aim We aimed to develop a new automated approach for quantifying visible brain injury from small vessel disease and brain atrophy in a single measure, the brain health index. Materials and methods We computed brain health index in N = 288 participants using voxel-based Gaussian mixture model cluster analysis of T1, T2, T2*, and FLAIR magnetic resonance imaging. We tested brain health index against a validated total small vessel disease visual score and white matter hyperintensity volumes in two patient groups (minor stroke, N = 157; lupus, N = 51) and against measures of brain atrophy in healthy participants (N = 80) using multiple regression. We evaluated associations with Addenbrooke's Cognitive Exam Revised in patients and with reaction time in healthy participants. Results The brain health index (standard beta = 0.20-0.59, P < 0.05) was significantly and more strongly associated with Addenbrooke's Cognitive Exam Revised, including at one year follow-up, than white matter hyperintensity volume (standard beta = 0.04-0.08, P > 0.05) and small vessel disease score (standard beta = 0.02-0.27, P > 0.05) alone in both patient groups. Further, the brain health index (standard beta = 0.57-0.59, P < 0.05) was more strongly associated with reaction time than measures of brain atrophy alone (standard beta = 0.04-0.13, P > 0.05) in healthy participants. Conclusions The brain health index is a new image analysis approach that may usefully capture combined visible brain damage in large-scale studies of ageing, neurovascular and neurodegenerative disease.

Widespread associations between trait conscientiousness and thickness of brain cortical regions.

The neural correlates of human personality have been of longstanding interest; however, most studies in the field have relied on modest sample sizes and few replicable results have been reported to date. We investigated relationships between personality and brain gray matter in a sample of generally healthy, older (mean age 73 years) adults from Scotland drawn from the Lothian Birth Cohort 1936. Participants (N = 578) completed a brain MRI scan and self-reported Big Five personality trait measures. Conscientiousness trait scores were positively related to brain cortical thickness in a range of regions, including bilateral parahippocampal gyrus, bilateral fusiform gyrus, left cingulate gyrus, right medial orbitofrontal cortex, and left dorsomedial prefrontal cortex. These associations - most notably in frontal regions - were modestly-to-moderately attenuated by the inclusion of biomarker variables assessing allostatic load and smoking status. None of the other personality traits showed robust associations with brain cortical thickness, nor did we observe any personality trait associations with cortical surface area and gray matter volume. These findings indicate that brain cortical thickness is associated with conscientiousness, perhaps partly accounted for by allostatic load and smoking status.

Brain cortical characteristics of lifetime cognitive ageing.

Regional cortical brain volume is the product of surface area and thickness. These measures exhibit partially distinct trajectories of change across the brain's cortex in older age, but it is unclear which cortical characteristics at which loci are sensitive to cognitive ageing differences. We examine associations between change in intelligence from age 11 to 73 years and regional cortical volume, surface area, and thickness measured at age 73 years in 568 community-dwelling older adults, all born in 1936. A relative positive change in intelligence from 11 to 73 was associated with larger volume and surface area in selective frontal, temporal, parietal, and occipital regions (r < 0.180, FDR-corrected q < 0.05). There were no significant associations between cognitive ageing and a thinner cortex for any region. Interestingly, thickness and surface area were phenotypically independent across bilateral lateral temporal loci, whose surface area was significantly related to change in intelligence. These findings suggest that associations between regional cortical volume and cognitive ageing differences are predominantly driven by surface area rather than thickness among healthy older adults. Regional brain surface area has been relatively underexplored, and is a potentially informative biomarker for identifying determinants of cognitive ageing differences.

Cognitive abilities, brain white matter hyperintensity volume, and structural network connectivity in older age.

OBJECTIVE: To assess brain structural connectivity in relation to cognitive abilities in healthy ageing, and the mediating effects of white matter hyper-intensity (WMH) volume. METHODS: MRI data were analysed in 558 members of the Lothian Birth Cohort 1936. Brains were segmented into 85 regions and combined with tractography to generate structural connectomes. WMH volume was quantified. Relationships between whole-brain connectivity, assessed using graph theory metrics, and four major domains of cognitive ability (visuospatial reasoning, verbal memory, information processing speed and crystallized ability) were investigated, as was the mediating effects of WMH volume on these relationships. RESULTS: Visuospatial reasoning was associated with network strength, mean shortest path length, and global efficiency. Memory was not associated with any network connectivity metric. Information processing speed and crystallized ability were associated with all network measures. Some relationships were lost when adjusted for mean network FA. WMH volume mediated 11%-15% of the relationships between most network measures and information processing speed, even after adjusting for mean network FA. CONCLUSION: Brain structural connectivity relates to visuospatial reasoning, information processing speed and crystallized ability, but not memory, in this relatively healthy age-homogeneous cohort of 73 year olds. When adjusted for mean FA across the network, most relationships are lost, except with information processing speed suggesting that the underlying topological network structure is related to this cognitive domain. Moreover, the connectome-processing speed relationship is partly mediated by WMH volume in this cohort. Hum Brain Mapp 39:622-632, 2018. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Brain structural differences between 73- and 92-year olds matched for childhood intelligence, social background, and intracranial volume.

Fully characterizing age differences in the brain is a key task for combating aging-related cognitive decline. Using propensity score matching on 2 independent, narrow-age cohorts, we used data on childhood cognitive ability, socioeconomic background, and intracranial volume to match participants at mean age of 92 years (n = 42) to very similar participants at mean age of 73 years (n = 126). Examining a variety of global and regional structural neuroimaging variables, there were large differences in gray and white matter volumes, cortical surface area, cortical thickness, and white matter hyperintensity volume and spatial extent. In a mediation analysis, the total volume of white matter hyperintensities and total cortical surface area jointly mediated 24.9% of the relation between age and general cognitive ability (tissue volumes and cortical thickness were not significant mediators in this analysis). These findings provide an unusual and valuable perspective on neurostructural aging, in which brains from the 8th and 10th decades of life differ widely despite the same cognitive, socioeconomic, and brain-volumetric starting points.