Biomarkers.

Background: Accelerated epigenetic ageing has been associated with various age-related health outcomes, but its relevance for dementia risk prediction is unclear. We investigated whether accelerated midlife epigenetic age associates with poor later-life brain health.

Methods: Participants were 230 individuals from Insight 46, drawn from the 1946 British Birth Cohort, a population-based study of individuals born in the first week of March 1946.

Public Health.

Background: In elite athletes, participation in sports associated with repetitive head injury exposure has been linked to an increased risk of neurodegeneration later in life. However, there has been limited study in more general populations. We aimed to investigate whether participation in such sports impacted outcomes relevant to brain health in a cohort of British-born older adults.

Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK.

Introduction: There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS.

Methods And Analysis: MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.

Peripheral hearing loss at age 70 predicts brain atrophy and associated cognitive change.

Background: Hearing loss has been proposed as a modifiable risk factor for dementia. However, the relationship between hearing, neurodegeneration, and cognitive change, and the extent to which pathological processes such as Alzheimer's disease and cerebrovascular disease influence these relationships, is unclear.

Methods: Data from 287 adults born in the same week of 1946 who underwent baseline pure tone audiometry (mean age=70.

Updating the study protocol: Insight 46 - a longitudinal neuroscience sub-study of the MRC National Survey of Health and Development - phases 2 and 3.

Background: Although age is the biggest known risk factor for dementia, there remains uncertainty about other factors over the life course that contribute to a person's risk for cognitive decline later in life. Furthermore, the pathological processes leading to dementia are not fully understood. The main goals of Insight 46-a multi-phase longitudinal observational study-are to collect detailed cognitive, neurological, physical, cardiovascular, and sensory data; to combine those data with genetic and life-course information collected from the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort); and thereby contribute to a better understanding of healthy ageing and dementia.

Rates of cortical thinning in Alzheimer's disease signature regions associate with vascular burden but not with β-amyloid status in cognitively normal adults at age 70.

Background: Consistent patterns of reduced cortical thickness have been identified in early Alzheimer's disease (AD). However, the pathological factors that influence rates of cortical thinning within these AD signature regions remain unclear.

Methods: Participants were from the Insight 46 substudy of the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort), a prospective longitudinal cohort study.

Neuroimaging, clinical and life course correlates of normal-appearing white matter integrity in 70-year-olds.

We investigate associations between normal-appearing white matter microstructural integrity in cognitively normal ∼70-year-olds and concurrently measured brain health and cognition, demographics, genetics and life course cardiovascular health. Participants born in the same week in March 1946 (British 1946 birth cohort) underwent PET-MRI around age 70. Mean standardized normal-appearing white matter integrity metrics (fractional anisotropy, mean diffusivity, neurite density index and orientation dispersion index) were derived from diffusion MRI.

Defining Peri-Operative Myocardial Injury during Cardiac Surgery Using High-Sensitivity Troponin T.

Objective: Cut-offs for high-sensitivity troponin (hs-Tn) elevations to define prognostically significant peri-operative myocardial injury (PMI) in cardiac surgery is not well-established. We evaluated the associations between peri-operative high-sensitivity troponin T (hs-TnT) elevations and 1-year all-cause mortality in patients undergoing cardiac surgery.

Methods: The prognostic significance of baseline hs-TnT and various thresholds for post-operative hs-TnT elevation at different time-points on 1-year all-cause mortality following cardiac surgery were assessed after adjusting for baseline hs-TnT and EuroSCORE in a post-hoc analysis of the ERICCA trial.

Visual dysfunction is a better predictor than retinal thickness for dementia in Parkinson's disease.

Background: Dementia is a common and devastating symptom of Parkinson's disease (PD). Visual function and retinal structure are both emerging as potentially predictive for dementia in Parkinson's but lack longitudinal evidence.

Methods: We prospectively examined higher order vision (skew tolerance and biological motion) and retinal thickness (spectral domain optical coherence tomography) in 100 people with PD and 29 controls, with longitudinal cognitive assessments at baseline, 18 months and 36 months.

Structural MRI predicts clinical progression in presymptomatic genetic frontotemporal dementia: findings from the GENetic Frontotemporal dementia Initiative cohort.

Biomarkers that can predict disease progression in individuals with genetic frontotemporal dementia are urgently needed. We aimed to identify whether baseline MRI-based grey and white matter abnormalities are associated with different clinical progression profiles in presymptomatic mutation carriers in the GENetic Frontotemporal dementia Initiative. Three hundred eighty-seven mutation carriers were included (160 , 160 , 67 ), together with 240 non-carrier cognitively normal controls.

A comprehensive assessment of age at menopause with well-characterized cognition at 70 years: A population-based British birth cohort.

Objectives: Associations between age at menopause and cognition post-menopause are examined to determine whether relationships are stronger for certain cognitive domains.

Study Design: Women from the Medical Research Council National Survey of Health and Development and its neuroscience sub-study, Insight 46, were included if they had known age at menopause (self-reported via questionnaire) and complete cognitive outcome data at age 69 (n = 746) or at Insight 46 wave I (n = 197). Multivariable linear regression analyses adjusting for life course confounders were run; interactions with menopause type (natural/surgical) and APOE-ε4 status were examined; and the potential contribution of hormone therapy was assessed.

Adulthood cognitive trajectories over 26 years and brain health at 70 years of age: findings from the 1946 British Birth Cohort.

Few studies can address how adulthood cognitive trajectories relate to brain health in 70-year-olds. Participants (n = 468, 49% female) from the 1946 British birth cohort underwent 18F-Florbetapir PET/MRI. Cognitive function was measured in childhood (age 8 years) and across adulthood (ages 43, 53, 60-64 and 69 years) and was examined in relation to brain health markers of β-amyloid (Aβ) status, whole brain and hippocampal volume, and white matter hyperintensity volume (WMHV).

Herpes simplex virus and rates of cognitive decline or whole brain atrophy in the Dominantly Inherited Alzheimer Network.

Objective: To investigate whether herpes simplex virus type 1 (HSV-1) infection was associated with rates of cognitive decline or whole brain atrophy among individuals from the Dominantly Inherited Alzheimer Network (DIAN).

Methods: Among two subsets of the DIAN cohort (age range 19.6-66.

Associations of β-Amyloid and Vascular Burden With Rates of Neurodegeneration in Cognitively Normal Members of the 1946 British Birth Cohort.

Background And Objectives: The goals of this work were to quantify the independent and interactive associations of β-amyloid (Aβ) and white matter hyperintensity volume (WMHV), a marker of presumed cerebrovascular disease (CVD), with rates of neurodegeneration and to examine the contributions of ε4 and vascular risk measured at different stages of adulthood in cognitively normal members of the 1946 British Birth Cohort.

Methods: Participants underwent brain MRI and florbetapir-Aβ PET as part of Insight 46, an observational population-based study. Changes in whole-brain, ventricular, and hippocampal volume were directly measured from baseline and repeat volumetric T1 MRI with the boundary shift integral.

Designing Multi-arm Multistage Adaptive Trials for Neuroprotection in Progressive Multiple Sclerosis.

There are few treatments shown to slow disability progression in progressive multiple sclerosis (PMS). One challenge has been efficiently testing the pipeline of candidate therapies from preclinical studies in clinical trials. Multi-arm multistage (MAMS) platform trials may accelerate evaluation of new therapies compared to traditional sequential clinical trials.

Assessing Neurofilaments as Biomarkers of Neuroprotection in Progressive Multiple Sclerosis: From the MS-STAT Randomized Controlled Trial.

Background And Objectives: Improved biomarkers of neuroprotective treatment are needed in progressive multiple sclerosis (PMS) to facilitate more efficient phase 2 trial design. The MS-STAT randomized controlled trial supported the neuroprotective potential of high-dose simvastatin in secondary progressive MS (SPMS). Here, we analyze serum from the MS-STAT trial to assess the extent to which neurofilament light (NfL) and neurofilament heavy (NfH), both promising biomarkers of neuroaxonal injury, may act as biomarkers of simvastatin treatment in SPMS.

Dissociable effects of -ε4 and β-amyloid pathology on visual working memory.

Although -ε4 carriers are at significantly higher risk of developing Alzheimer's disease than non-carriers, controversial evidence suggests that -ε4 might confer some advantages, explaining the survival of this gene (antagonistic pleiotropy). In a population-based cohort born in one week in 1946 (assessed aged 69-71), we assessed differential effects of -ε4 and β-amyloid pathology (quantified using F-Florbetapir-PET) on visual working memory (object-location binding). In 398 cognitively normal participants, -ε4 and β-amyloid had opposing effects on object identification, predicting better and poorer recall respectively.

Visual short-term memory impairments in presymptomatic familial Alzheimer's disease: A longitudinal observational study.

Visual short-term memory (VSTM) deficits including VSTM binding have been associated with Alzheimer's disease (AD) from preclinical to dementia stages, cross-sectionally. Yet, longitudinal investigations are lacking. The objective of this study was to evaluate VSTM function longitudinally and in relation to expected symptom onset in a cohort of familial Alzheimer's disease.

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.

Decoding expectation and surprise in dementia: the paradigm of music.

Making predictions about the world and responding appropriately to unexpected events are essential functions of the healthy brain. In neurodegenerative disorders, such as frontotemporal dementia and Alzheimer's disease, impaired processing of 'surprise' may underpin a diverse array of symptoms, particularly abnormalities of social and emotional behaviour, but is challenging to characterize. Here, we addressed this issue using a novel paradigm: music.

Comparison of clinical rating scales in genetic frontotemporal dementia within the GENFI cohort.

Background: Therapeutic trials are now underway in genetic forms of frontotemporal dementia (FTD) but clinical outcome measures are limited. The two most commonly used measures, the Clinical Dementia Rating (CDR)+National Alzheimer's Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) and the FTD Rating Scale (FRS), have yet to be compared in detail in the genetic forms of FTD.

Methods: The CDR+NACC FTLD and FRS were assessed cross-sectionally in 725 consecutively recruited participants from the Genetic FTD Initiative: 457 mutation carriers (77 microtubule-associated protein tau (, 187 , 193 ) and 268 family members without mutations (non-carrier control group).

Variability in the type and layer distribution of cortical Aβ pathology in familial Alzheimer's disease.

Familial Alzheimer's disease (FAD) is caused by autosomal dominant mutations in the PSEN1, PSEN2 or APP genes, giving rise to considerable clinical and pathological heterogeneity in FAD. Here we investigate variability in clinical data and the type and distribution of Aβ pathologies throughout the cortical layers of different FAD mutation cases. Brain tissue from 20 FAD cases [PSEN1 pre-codon 200 (n = 10), PSEN1 post-codon 200 (n = 6), APP (n = 4)] were investigated.