Nomograms of human hippocampal volume shifted by polygenic scores

Nomograms are important clinical tools applied widely in both developing and aging populations. They are generally constructed as normative models identifying cases as outliers to a distribution of healthy controls. Currently used normative models do not account for genetic heterogeneity. Hippocampal Volume (HV) is a key endophenotype for many brain disorders. Here, we examine the impact of genetic adjustment on HV nomograms and the translational ability to detect dementia patients. Using imaging data from 35,686 healthy subjects aged 44 to 82 from the UK BioBank (UKB), we built HV nomograms using gaussian process regression (GPR), which - compared to a previous method - extended the application age by 20 years, including dementia critical age ranges. Using HV Polygenic Scores (HV-PGS), we built genetically adjusted nomograms from participants stratified into the top and bottom 30% of HV-PGS. This shifted the nomograms in the expected directions by ~100 mm3 (2.3% of the average HV), which equates to 3 years of normal aging for a person aged ~65. Clinical impact of genetically adjusted nomograms was investigated by comparing 818 subjects from the AD neuroimaging (ADNI) database diagnosed as either cognitively normal (CN), having mild cognitive impairment (MCI) or Alzheimer's disease patients (AD). While no significant change in the survival analysis was found for MCI-to-AD conversion, an average of 68% relative decrease was found in intra-diagnostic-group variance, highlighting the importance of genetic adjustment in untangling phenotypic heterogeneity

Lifecourse investigation of the cumulative impact of adversity on cognitive function in old age and the mediating role of mental health: longitudinal birth cohort study

Objective: To investigate the accumulation of adversities (duration of exposure to any, economic, psychosocial) across the lifecourse (birth to 63 years) on cognitive function in older age, and the mediating role of mental health. // Design: National birth cohort study. // Setting: Great Britain. // Participants: 5362 singleton births within marriage in England, Wales and Scotland born within 1 week of March 1946, of which 2131 completed at least 1 cognitive assessment. // Main outcome measures: Cognitive assessments included the Addenbrooke’s Cognitive Examination-III, as a measure of cognitive state, processing speed (timed-letter search task), and verbal memory (word learning task) at 69 years. Scores were standardised to the analytical sample. Mental health at 60–64 years was assessed using the 28-item General Health Questionnaire, with scores standardised to the analytical sample. // Results: After adjusting for sex, increased duration of exposure to any adversity was associated with decreased performance on cognitive state (β=−0.39; 95% CI −0.59 to –0.20) and verbal memory (β=−0.45; 95% CI −0.63 to –0.27) at 69 years, although these effects were attenuated after adjusting for further covariates (childhood cognition and emotional problems, educational attainment). Analyses by type of adversity revealed stronger associations from economic adversity to verbal memory (β=−0.54; 95% CI −0.70 to –0.39), with a small effect remaining even after adjusting for all covariates (β=−0.18; 95% CI −0.32 to –0.03), and weaker associations from psychosocial adversity. Causal mediation analyses found that mental health mediated all associations between duration of exposure to adversity (any, economic, psychosocial) and cognitive function, with around 15% of the total effect of economic adversity on verbal memory attributable to mental health. // Conclusions: Improving mental health among older adults has the potential to reduce cognitive impairments, as well as mitigate against some of the effect of lifecourse accumulation of adversity on cognitive performance in older age

Correction to: Grip strength from midlife as an indicator of later-life brain health and cognition: evidence from a British birth cohort.

BACKGROUND: Grip strength is an indicator of physical function with potential predictive value for health in ageing populations. We assessed whether trends in grip strength from midlife predicted later-life brain health and cognition. METHODS: 446 participants in an ongoing British birth cohort study, the National Survey of Health and Development (NSHD), had their maximum grip strength measured at ages 53, 60-64, and 69, and subsequently underwent neuroimaging as part of a neuroscience sub-study, referred to as "Insight 46", at age 69-71. A group-based trajectory model identified latent groups of individuals in the whole NSHD cohort with below- or above-average grip strength over time, plus a reference group. Group assignment, plus standardised grip strength levels and change from midlife were each related to measures of whole-brain volume (WBV) and white matter hyperintensity volume (WMHV), plus several cognitive tests. Models were adjusted for sex, body size, head size (where appropriate), sociodemographics, and behavioural and vascular risk factors. RESULTS: Lower grip strength from midlife was associated with smaller WBV and lower matrix reasoning scores at age 69-71, with findings consistent between analysis of individual time points and analysis of trajectory groups. There was little evidence of an association between grip strength and other cognitive test scores. Although greater declines in grip strength showed a weak association with higher WMHV at age 69-71, trends in the opposite direction were seen at individual time points with higher grip strength at ages 60-64, and 69 associated with higher WMHV. CONCLUSIONS: This study provides preliminary evidence that maximum grip strength may have value in predicting brain health. Future work should assess to what extent age-related declines in grip strength from midlife reflect concurrent changes in brain structure

A lifecourse approach in examining the association between accumulation of adversity and mental health in older adulthood

BACKGROUND: There is evidence for a cumulative effect of adversities on mental health, however, less is known on the accumulating duration of exposure to adversity across the lifecourse on mental health in older adults. METHODS: Using data from the 1946 British birth cohort study (N = 2745), we examined associations between the accumulation of adversity (birth-63 years) and mental health (emotional symptom, life satisfaction, affective wellbeing) in older adults (63-69 years). Accumulation of adversity was assessed as the number of adversities and duration of exposure (number of lifecourse stages exposed to any, economic, psychosocial, or physical adversity). Linear regression tested their association with mental health, adjusted for sex, childhood cognition and emotional problems, and educational attainment. RESULTS: Increased number of adversities was associated with increased emotional symptoms (β = 0.08 [0.06, 0.10]), decreased life satisfaction (β = -0.14 [-0.16, -0.12]) and decreased affective wellbeing (β = -0.08 [-0.10, -0.06]). Each additional duration of exposure was associated with a 0.38 [0.12, 0.65] standard deviation (SD) increase in emotional symptoms, and a - 0.68 [-0.96, -0.39] and -0.43 SD [-0.68, -0.18] decrease in life satisfaction and affective wellbeing, respectively. Life satisfaction showed stronger associations with economic and psychosocial compared to physical adversity. LIMITATIONS: Some limitations include selective drop-out and lack of ethnic diversity. CONCLUSIONS: Efforts to improve mental health in older adults should focus on reducing the number of adversities, as well as considering previous exposure across different lifecourse stages, to prevent adversities from becoming chronic. Future research should also consider the clustering and co-occurrence of different adversities across the lifecourse

Distinct patterns of neurodegeneration after TBI and in Alzheimer's disease

INTRODUCTION: Traumatic brain injury (TBI) is a dementia risk factor, with Alzheimer's disease (AD) more common following injury. Patterns of neurodegeneration produced by TBI can be compared to AD and aging using volumetric MRI. METHODS: A total of 55 patients after moderate to severe TBI (median age 40), 45 with AD (median age 69), and 61 healthy volunteers underwent magnetic resonance imaging over 2 years. Atrophy patterns were compared. RESULTS: AD patients had markedly lower baseline volumes. TBI was associated with increased white matter (WM) atrophy, particularly involving corticospinal tracts and callosum, whereas AD rates were increased across white and gray matter (GM). Subcortical WM loss was shared in AD/TBI, but deep WM atrophy was TBI-specific and cortical atrophy AD-specific. Post-TBI atrophy patterns were distinct from aging, which resembled AD. DISCUSSION: Post-traumatic neurodegeneration 1.9-4.0 years (median) following moderate-severe TBI is distinct from aging/AD, predominantly involving central WM. This likely reflects distributions of axonal injury, a neurodegeneration trigger. HIGHLIGHTS: We compared patterns of brain atrophy longitudinally after moderate to severe TBI in late-onset AD and healthy aging. Patients after TBI had abnormal brain atrophy involving the corpus callosum and other WM tracts, including corticospinal tracts, in a pattern that was specific and distinct from AD and aging. This pattern is reminiscent of axonal injury following TBI, and atrophy rates were predicted by the extent of axonal injury on diffusion tensor imaging, supporting a relationship between early axonal damage and chronic neurodegeneration

ASL-incorporated pharmacokinetic modelling of PET data with reduced acquisition time: Application to amyloid imaging

Pharmacokinetic analysis of Positron Emission Tomography (PET) data typically requires at least one hour of image acquisition, which poses a great disadvantage in clinical practice. In this work, we propose a novel approach for pharmacokinetic modelling with significantly reduced PET acquisition time, by incorporating the blood flow information from simultaneously acquired arterial spin labelling (ASL) magnetic resonance imaging (MRI). A relationship is established between blood flow, measured by ASL, and the transfer rate constant from plasma to tissue of the PET tracer, leading to modified PET kinetic models with ASL-derived flow information. Evaluation on clinical amyloid imaging data from an Alzheimer’s disease (AD) study shows that the proposed approach with the simplified reference tissue model can achieve amyloid burden estimation from 30 min [18F]florbetapir PET data and 5 min simultaneous ASL MR data, which is comparable with the estimation from 60 min PET data (mean error=−0.03). Conversely, standardised uptake value ratio (SUVR), the alternative measure from the data showed a positive bias in areas of higher amyloid burden (mean error=0.07)