Injections of hope: supporting participants in clinical trials

Understanding hope and better appreciating the personal investments of trial participants could improve patient experience and trial design, argue Emma Harding, Catherine Mummery, and colleague

Video Conferencing Peer Support and Rarer Forms of Dementia: An Exploration of Family Carers’ Positive Experiences

Little is known regarding the nuanced experiences of family carers for people living with rare dementias (PLWRD), with no known literature exploring their positive experiences of caring discussed within peer support group settings. This article explores family carers of PLWRD’s positive experiences reported in video conferencing peer support groups. Six peer support group sessions involving a total of nine participants were qualitatively analysed using thematic analysis, guided by the conceptual framework of positive aspects of caring (CFPAC) (Carbonneau et al., 2010). Six themes were identified: (1) Protecting, maintaining, enjoying and finding strength in their relationship with the PLWRD; (2) Using tools and resources in response to challenges; (3) Positive impact of interactions and others’ responses to the dementia; (4) Overcoming barriers to taking a break while maintaining their wellbeing, (5) Maintaining positive outlooks and showing psychological resilience in adversity; and (6) Attributing meaning to the caring role. This article highlights family carers of PLWRD’s positive psychological, physical and social resources, balanced against the challenges of caring and maintaining their wellbeing, and identifies ways of promoting family carers’ positive caring experiences and resources within healthcare and supportive settings

Amyloid ? influences the relationship between cortical thickness and vascular load.

INTRODUCTION: Cortical thickness has been proposed as a biomarker of Alzheimer's disease (AD)- related neurodegeneration, but the nature of its relationship with amyloid beta (A?) deposition and white matter hyperintensity volume (WMHV) in cognitively normal adults is unclear. METHODS: We investigated the influences of A? status (negative/positive) and WMHV on cortical thickness in 408 cognitively normal adults aged 69.2 to 71.9 years who underwent 18F-Florbetapir positron emission tomography (PET) and structural magnetic resonance imaging (MRI). Two previously defined Alzheimer's disease (AD) cortical signature regions and the major cortical lobes were selected as regions of interest (ROIs) for cortical thickness. RESULTS: Higher WMHV, but not A? status, predicted lower cortical thickness across all participants, in all ROIs. Conversely, when A?-positive participants were considered alone, higher WMHV predicted higher cortical thickness in a temporal AD-signature region. DISCUSSION: WMHV may differentially influence cortical thickness depending on the presence or absence of A?, potentially reflecting different pathological mechanisms

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=70.6 years) and two time point cognitive assessment/multimodal brain imaging (mean interval 2.4 years) were analysed. Hearing impairment at baseline was defined as a pure tone average of greater than 25 decibels in the best hearing ear. Rates of change for whole brain, hippocampal and ventricle volume were estimated from structural MRI using the Boundary Shift Integral. Cognition was assessed using the Pre-clinical Alzheimer's Cognitive Composite. Regression models were performed to evaluate how baseline hearing impairment associated with subsequent brain atrophy and cognitive decline after adjustment for a range of confounders including baseline β-amyloid deposition and white matter hyperintensity volume. RESULTS: 111 out of 287 participants had hearing impairment. Compared with those with preserved hearing, hearing impaired individuals had faster rates of whole brain atrophy, and worse hearing (higher pure tone average) predicted faster rates of hippocampal atrophy. In participants with hearing impairment, faster rates of whole brain atrophy predicted greater cognitive change. All observed relationships were independent of β-amyloid deposition and white matter hyperintensity volume. CONCLUSIONS: Hearing loss may influence dementia risk via pathways distinct from those typically implicated in Alzheimer's and cerebrovascular disease in cognitively unimpaired older adults

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

We investigate associations between normal-appearing white matter (NAWM) 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 NAWM integrity metrics (fractional anisotropy (FA), mean diffusivity (MD), neurite density index (NDI) and orientation dispersion index (ODI)) were derived from diffusion MRI. Linear regression was used to test associations between NAWM metrics and (1) concurrent measures, including whole brain volume, white matter hyperintensity volume (WMHV), PET amyloid and cognition; (2) the influence of demographic and genetic predictors, including sex, childhood cognition, education, socioeconomic position, and genetic risk for Alzheimer’s Disease (APOE-ε4); (3) systolic and diastolic blood pressure and cardiovascular health (FHS-CVS) across adulthood. Sex interactions were tested. Statistical significance included false discovery rate correction (5%). 362 participants met inclusion criteria (mean age 70 years, 49% female). Higher WMHV was associated with lower FA (b=-0.09 [95%CI:-0.11, -0.06] p<0.01), NDI (b=-0.17 [-0.22, -0.12] p<0.01), and higher MD (b=0.14 [-0.10, -0.17] p<0.01); amyloid (in men) was associated with lower FA (b=-0.04 [-0.08, -0.01] p=0.03) and higher MD (b=0.06 [0.01,0.11] p=0.02). FHS-CVS in later-life (age 69) was associated with NAWM [lower FA (b=-0.06 [-0.09, -0.02] p<0.01), NDI (b=-0.10 [-0.17, -0.03] p<0.01), and higher MD (b=0.09 [0.04,0.14] p<0.01). Significant sex interactions (p<0.05) emerged for midlife cardiovascular health (age 53) and NAWM at 70: marginal effect plots demonstrated, in women only, NAWM was associated with higher midlife FHS-CVS (lower FA and NDI), midlife systolic (lower FA, NDI, and higher MD), and diastolic (lower FA and NDI) blood pressure, and greater blood pressure change between 43 and 53 years (lower FA and NDI), independently of WMHV. In summary, poorer NAWM microstructural integrity in ∼70-year-olds was associated with measures of cerebral small vessel disease, amyloid (in males) and later-life cardiovascular health, demonstrating how NAWM can provide additional information to overt white matter disease. Our findings further show that greater midlife cardiovascular risk and higher blood pressure were associated with poorer NAWM microstructural integrity in females only, suggesting that women’s brains may be more susceptible to the effects of midlife blood pressure and cardiovascular health

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

OBJECTIVE: To quantify the independent and interactive associations of amyloid-β (Aβ) and white matter hyperintensity volume (WMHV) - a marker of presumed cerebrovascular disease (CVD) - with rates of neurodegeneration, and to examine the contributions of APOE 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 positron emission tomography 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 using the Boundary Shift Integral. Linear regression was used to test associations with: baseline Aβ deposition; baseline WMHV; APOE ε4; and office-based Framingham heart study-cardiovascular risk scores (FHS-CVS) and systolic blood pressure (BP) at ages 36, 53 and 69 years. RESULTS: 346 cognitively normal participants (mean [SD] age at baseline scan 70.5 [0.6] years; 48% female) had high-quality T1 MRI data from both time-points (mean [SD] scan interval 2.4 [0.2] years). Being Aβ positive at baseline was associated with 0.87 ml/year faster whole brain atrophy (95% CI 0.03, 1.72), 0.39 ml/year greater ventricular expansion (95% CI 0.16, 0.64) and 0.016 ml/year faster hippocampal atrophy (95% CI 0.004, 0.027), while each 10 ml additional WMHV at baseline was associated with 1.07 ml/year faster whole brain atrophy (95% CI 0.47, 1.67), 0.31 ml/year greater ventricular expansion (95% CI 0.13, 0.60) and 0.014 ml/year faster hippocampal atrophy (95% CI 0.006, 0.022). These contributions were independent and there was no evidence that Aβ and WMHV interacted in their effects. There were no independent associations of APOE ε4 with rates of neurodegeneration after adjusting for Aβ status and WMHV, and no clear relationships between FHS-CVS or systolic BP and rates of neurodegeneration when assessed across the whole sample, nor any evidence that they acted synergistically with Aβ. CONCLUSIONS: Aβ and presumed CVD have distinct and additive effects on rates of neurodegeneration in cognitively normal elderly. These findings have implications for the use of MRI measures as biomarkers of neurodegeneration and emphasize the importance of risk management and early intervention targeting both pathways

Concussion and long-term cognitive function among rugby players-The BRAIN Study.

OBJECTIVE: The BRAIN Study was established to assess the associations between self-reported concussions and cognitive function among retired rugby players. METHODS: Former elite-level male rugby union players (50+ years) in England were recruited. Exposure to rugby-related concussion was collected using the BRAIN-Q tool. The primary outcome measure was the Preclinical Alzheimer Cognitive Composite (PACC). Linear regressions were conducted for the association between concussion and PACC score, adjusting for confounders. RESULTS: A total of 146 participants were recruited. The mean (standard deviation) length of playing career was 15.8 (5.4) years. A total of 79.5% reported rugby-related concussion(s). No association was found between concussion and PACC (β -0.03 [95% confidence interval (CI): -1.31, 0.26]). However, participants aged 80+ years reporting 3+ concussions had worse cognitive function than those without concussion (β -1.04 [95% CI: -1.62, -0.47]). CONCLUSIONS: Overall there was no association between concussion and cognitive function; however, a significant interaction with age revealed an association in older participants

Pure tone audiometry and cerebral pathology in healthy older adults.

BACKGROUND: Hearing impairment may be a modifiable risk factor for dementia. However, it is unclear how hearing associates with pathologies relevant to dementia in preclinical populations. METHODS: Data from 368 cognitively healthy individuals born during 1 week in 1946 (age range 69.2-71.9 years), who underwent structural MRI, 18F-florbetapir positron emission tomography, pure tone audiometry and cognitive testing as part of a neuroscience substudy the MRC National Survey of Health and Development were analysed. The aim of the analysis was to investigate whether pure tone audiometry performance predicted a range of cognitive and imaging outcomes relevant to dementia in older adults. RESULTS: There was some evidence that poorer pure tone audiometry performance was associated with lower primary auditory cortex thickness, but no evidence that it predicted in vivo β-amyloid deposition, white matter hyperintensity volume, hippocampal volume or Alzheimer's disease-pattern cortical thickness. A negative association between pure tone audiometry and mini-mental state examination score was observed, but this was no longer evident after excluding a test item assessing repetition of a single phrase. CONCLUSION: Pure tone audiometry performance did not predict concurrent β-amyloid deposition, small vessel disease or Alzheimer's disease-pattern neurodegeneration, and had limited impact on cognitive function, in healthy adults aged approximately 70 years

?-amyloid influences the relationship between cortical thickness and vascular load

Introduction: Cortical thickness has been proposed as a biomarker of Alzheimer�s disease related neurodegeneration, but the nature of its relationship with amyloid (A?) deposition and white matter hyperintensity volume (WMHV) in cognitively normal adults is unclear. Methods: We investigated the influences of A?-status (negative/positive) and WMHV on cortical thickness in 408 cognitively normal adults aged 69.2-71.9 years who underwent 18F-Florbetapir PET and structural MRI. Two previously defined Alzheimer�s disease cortical signature regions and the major cortical lobes were selected as regions of interest for cortical thickness. Results: Higher white matter hyperintensity volume, but not A?-status, predicted lower cortical thickness across all participants, in all regions of interest. Conversely, when A?-positive participants were considered alone, higher white matter hyperintensity volume predicted higher cortical thickness in a temporal Alzheimer�s disease-signature region. Discussion: WMHV may differentially influence cortical thickness depending on the presence or absence of ?-amyloid, potentially reflecting different pathological mechanism