Imaging and molecular mechanisms of Alzheimer's fisease: a review

Alzheimer’s disease is the most common form of dementia and is a significant burden for affected patients, carers, and health systems. Great advances have been made in understanding its pathophysiology, to a point that we are moving from a purely clinical diagnosis to a biological one based on the use of biomarkers. Among those, imaging biomarkers are invaluable in Alzheimer’s, as they provide an in vivo window to the pathological processes occurring in Alzheimer’s brain. While some imaging techniques are still under evaluation in the research setting, some have reached widespread clinical use. In this review, we provide an overview of the most commonly used imaging biomarkers in Alzheimer’s disease, from molecular PET imaging to structural MRI, emphasising the concept that multimodal imaging would likely prove to be the optimal tool in the future of Alzheimer’s research and clinical practice

APOE ɛ4 exacerbates age-dependent deficits in cortical microstructure

The apolipoprotein E ɛ4 allele is the primary genetic risk factor for the sporadic type of Alzheimer’s disease. However, the mechanisms by which apolipoprotein E ɛ4 are associated with neurodegeneration are still poorly understood. We applied the Neurite Orientation Dispersion Model to characterize the effects of apolipoprotein ɛ4 and its interactions with age and education on cortical microstructure in cognitively normal individuals. Data from 1954 participants were included from the PREVENT-Dementia and ALFA (ALzheimer and FAmilies) studies (mean age = 57, 1197 non-carriers and 757 apolipoprotein E ɛ4 carriers). Structural MRI datasets were processed with FreeSurfer v7.2. The Microstructure Diffusion Toolbox was used to derive Orientation Dispersion Index maps from diffusion MRI datasets. Primary analyses were focused on (i) the main effects of apolipoprotein E ɛ4, and (ii) the interactions of apolipoprotein E ɛ4 with age and education on lobar and vertex-wise Orientation Dispersion Index and implemented using Permutation Analysis of Linear Models. There were apolipoprotein E ɛ4 × age interactions in the temporo-parietal and frontal lobes, indicating steeper age-dependent Orientation Dispersion Index changes in apolipoprotein E ɛ4 carriers. Steeper age-related Orientation Dispersion Index declines were observed among apolipoprotein E ɛ4 carriers with lower years of education. We demonstrated that apolipoprotein E ɛ4 worsened age-related Orientation Dispersion Index decreases in brain regions typically associated with atrophy patterns of Alzheimer’s disease. This finding also suggests that apolipoprotein E ɛ4 may hasten the onset age of dementia by accelerating age-dependent reductions in cortical Orientation Dispersion Index

What do we know about the risks of developing dementia after traumatic brain injury?

Traumatic brain injury (TBI) is considered to be a risk factor for the later development of dementia, but although the evidence dates back to the early 20th century, the nature of any association and its mechanistic pathways remain unclear. There has been greater focus on this subject over recent years, in part because of increasing reports around sports-related TBIs, especially in the US. Differences in research methods and clinical sampling remain the primary reason for the variable findings, although there is clearly increased prevalence of neurodegenerative disorders in general. Duration of follow up, definition of both TBI and dementia, and differences in the extent to which other dementia risk factors are controlled, as well as concerns about medical record accuracy are all issues yet to be resolved in TBI research, as is an absence pathological evidence. In addition, TBI has been reported to initiate a cascade of pathological processes related to several neurodegenerative disorders, and as such, it is likely that the risks vary between individuals. Given the evidence that dementia risk may increase with injury severity and frequency, a detailed account of age and type of injury, as well as lifetime TBI exposure is essential to document in future studies, and further longitudinal research with biomarker assessments are needed

Women in science: achievements and ambitions

International Women's Day will be celebrated on 8 March 2021. Much has changed in the modern world, but it is still a fact that women are underrepresented in many sectors; this is especially true in science and research. Colleagues from the Oxford Brain Health Clinical Trials Unit reflect on the historical contribution of women in STEM and what future challenges and successes may lay ahead

Clinical trials: from problem child to the driving force of medical advancement

Clinical trials are conducted to find better ways to prevent, screen for, diagnose or treat human disease. The development of clinical trials throughout history has built the foundation for ethically and scientifically robust research. As our healthcare needs have evolved, so have clinical trials and the standards by which they are run. Vanessa Raymont and colleagues explore the past, present and future of the clinical trial

Rapid commentary: Ethical implications for clinical trialists and patients associated with COVID-19 research Delanerolle G, Rathod S, Elliot K, Ramakrishnan R, Thayanandan T, Sandle N, Haque N, Raymont V, Phiri P. Rapid commentary: Ethical implications for clinical trialists and patients associated with COVID-19 research

Pandemics disrupt clinical trials worldwide, with lasting effects on research. It can severely impact clinical trialists ability to conduct safe and ethically uncompromised trials. Hence, the mounting pressure results in ethically and morally distressing decisions faced by clinical trial professionals during pandemic situations. Whilst clinical trialists attempt to think about preparedness and responses during a pandemic, the need to have an ethical framework that has real-world applicability is imperative. Pandemics are a challenging time for all, however, the safety and access to support for clinical trialists and patients within clinical trials should be at the forefront for their organisations and the government

Lifetime TBI and cognitive domain deficits in late life: The PROTECT-TBI cohort study

This is the author accepted manuscript.Data sharing statement: Deidentified participant data and data dictionary for the PROTECT study is available on request from the PROTECT study team at the University of Exeter ([email protected]). Access is available after approval of a proposal and a signed data access agreement.TBI causes cognitive impairment but it remains contested which cognitive domains are most affected. Further, moderate-severe TBI is known to be deleterious, but studies of mild TBI (mTBI) show a greater mix of negative and positive findings . This study examines the longerterm cognitive effects of TBI severity and number of mild TBI in later life. We examined a subset (n=15,764) of the PROTECT study, a cohort assessing risk factors for cognitive decline (ages between 50 and 90). Participants completed cognitive assessments annually for four years. Cognitive tests were grouped using a Principal Components Analysis (PCA) into working memory, episodic memory, attention, processing speed and executive function. Lifetime TBI severity and number were retrospectively recalled by participants using the Brain Injury Screening Questionnaire (BISQ). Linear Mixed Models examined the effect of severity of head injury (non-TBI head strike, mild TBI (mTBI) and moderate-severe TBI) and number of mTBI at baseline and over time. mTBI was considered as a continuous and categorical variable (groups: 0 mTBI, 1 mTBI, 2 mTBIs, 3 mTBIs and 4+ mTBIs). Of the participants 5,725 (36.3%) reported at least one mild TBI and 510 (3.2%) at least one moderate-severe TBI, while 3,711 (23.5%) had suffered at worst a non-TBI head strike and 5,818 (32.9%) reported no head injuries. The participants had suffered their last reported head injury an average (SD) of 29.6 (20.0) years prior to the study. Regarding outcomes, there was no worsening in longitudinal cognitive trajectories over the study duration but at baseline there were significant cognitive deficits associated with TBI. At baseline, compared to those without head injury, individuals reporting at least one moderate-severe TBI had significantly poorer attention (B=-0.163, p<0.001), executive scores (B=-0.151, p=0.004) and processing speed (B=-0.075, p=0.033). Those who had suffered at least a single mTBI also demonstrated significantly poorer attention scores at baseline compared to the no head injury group (B=-0.052, p=0.001). Compared to those with no mTBI, those in the 3 mTBI group manifested poorer baseline executive function (B=-0.149, p=0.025) and attention scores (B=-0.085, p=0.015). At baseline, those who had suffered 4 or more mild TBIs demonstrated poorer attention (B=-0.135, p<0.001), processing speed (B=-0.072, p=0.009) and working memory (B=-0.052, p=0.036), compared to those reporting no mTBI. TBI is associated with fixed, dose, and severitydependent cognitive deficits. The most sensitive cognitive domains are attention and executive function, with approximately double the effect compared to processing speed and working memory. Post-TBI cognitive rehabilitation should be targeted appropriately to domain-specific effects. Significant long-term cognitive deficits were associated with 3 lifetime mTBI, a critical consideration when counselling individuals post-TBI about continuing high-risk activities.National Institute for Health Researc

Lifetime Traumatic Brain Injury and Cognitive Domain Deficits in Late Life: The PROTECT-TBI Cohort Study

Data sharing statement: Deidentified participant data and data dictionary for the PROTECT study is available on request from the PROTECT study team at the University of Exeter ([email protected]). Access is available after approval of a proposal and a signed data access agreement.Traumatic brain injury (TBI) causes cognitive impairment but it remains contested regarding which cognitive domains are most affected. Further, moderate-severe TBI is known to be deleterious, but studies of mild TBI (mTBI) show a greater mix of negative and positive findings. This study examines the longer-term cognitive effects of TBI severity and number of mTBIs in later life. We examined a subset (n = 15,764) of the PROTECT study, a cohort assessing risk factors for cognitive decline (ages between 50 and 90 years). Participants completed cognitive assessments annually for 4 years. Cognitive tests were grouped using a principal components analysis (PCA) into working memory, episodic memory, attention, processing speed, and executive function. Lifetime TBI severity and number were retrospectively recalled by participants using the Brain Injury Screening Questionnaire (BISQ). Linear mixed models (LMMs) examined the effect of severity of head injury (non-TBI head strike, mTBI, and moderate-severe TBI) and number of mTBI at baseline and over time. mTBI was considered as a continuous and categorical variable (groups: 0 mTBI, 1 mTBI, 2 mTBIs, 3 mTBIs, and 4+ mTBIs). Of the participants 5725 (36.3%) reported at least one mTBI and 510 (3.2%) at least one moderate-severe TBI, whereas 3711 (23.5%) had suffered at worst a non-TBI head strike and 5818 (32.9%) reported no head injuries. The participants had suffered their last reported head injury an average (standard deviation, SD) of 29.6 (20.0) years prior to the study. Regarding outcomes, there was no worsening in longitudinal cognitive trajectories over the study duration but at baseline there were significant cognitive deficits associated with TBI. At baseline, compared with those without head injury, individuals reporting at least one moderate-severe TBI had significantly poorer attention (B = −0.163, p< 0.001), executive scores (B = −0.151, p = 0.004), and processing speed (B = −0.075, p = 0.033). Those who had suffered at least a single mTBI also demonstrated significantly poorer attention scores at baseline compared with the no head injury group (B = −0.052, p = 0.001). Compared with those with no mTBI, those in the 3 mTBI group manifested poorer baseline executive function (B = −0.149, p = 0.025) and attention scores (B = −0.085, p = 0.015). At baseline, those who had suffered four or more mTBIs demonstrated poorer attention (B = −0.135, p < 0.001), processing speed (B = −0.072, p = 0.009), and working memory (B = −0.052, p = 0.036), compared with those reporting no mTBI. TBI is associated with fixed, dose, and severity-dependent cognitive deficits. The most sensitive cognitive domains are attention and executive function, with approximately double the effect compared with processing speed and working memory. Post-TBI cognitive rehabilitation should be targeted appropriately to domain-specific effects. Significant long-term cognitive deficits were associated with three or more lifetime mTBIs, a critical consideration when counseling individuals post-TBI about continuing high-risk activities.This paper represents an independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. This research was also supported by the NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula

An evaluation of the mental health impact of SARS-CoV-2 on patients, general public and healthcare professionals: A systematic review and meta-analysis

Background: The global impact of COVID-19 pandemic continues to affect the lives of billions of people with recurrent waves. Healthcare systems are struggling to manage pre-existing patient care and recurring covid-19 demands. As a result, we evaluated the mental health impact using systematic review and meta-analysis. Methods: A comprehensive search was undertaken from April 2020 to 22nd January 2021 using multiple electronic databases. A systematic review protocol was developed and published on PROSPERO registration; CRD42020181481. A random-effects model was used to compute pooled estimates of anxiety, depression, PTSD, insomnia and suicidal thoughts. Findings: Our search yielded 11,295 studies and of those 287 met the inclusion criteria. The meta-analysis of 206 studies revealed minimal differences in prevalence of anxiety, depression, and PTSD among HCPs compared with the public during the pandemic but higher prevalence of suicidal thoughts/ideation or self-harm (11% vs 5.8%) and lower prevalence of wellbeing (28.2% vs 52.6%) among the public compared to HCPs. Interpretation: The pandemic has led to a high mental health burden especially amongst HCPs and higher suicidal ideation and lower wellbeing in general public which warrants further investigation and management globally. These findings highlight an emerging critical public health issue that requires urgent solutions