ABSTRACT
Importance: Traumatic brain injuries (TBI) represent an important, potentially modifiable risk factor for dementia. Despite frequently observed vascular imaging changes in individuals with TBI, the relationships between TBI-associated changes in brain imaging and clinical outcomes have largely been overlooked in community cases of TBI. Objective: To assess whether TBI are associated with and interact with midlife changes in neuroimaging and clinical features in otherwise healthy individuals. Design, Setting, and Participants: This cross-sectional analysis used baseline data from the PREVENT Dementia program collected across 5 sites in the UK and Ireland between 2014 and 2020. Eligible participants were cognitively healthy midlife adults aged between 40 and 59 years. Data were analyzed between January 2023 and April 2024. Exposure: Lifetime TBI history was assessed using the Brain Injury Screening Questionnaire. Main Outcomes and Measures: Cerebral microbleeds and other markers of cerebral small vessel disease (white matter hyperintensities [WMH], lacunes, perivascular spaces) were assessed on 3T magnetic resonance imaging. Clinical measures were cognition, sleep, depression, gait, and cardiovascular disease (CVD) risk, assessed using Computerized Assessment of Information Processing (COGNITO), Pittsburgh Sleep Quality Index, Center for Epidemiologic Studies Depression Scale, clinical interviews, and the Framingham Risk Score, respectively. Results: Of 617 participants (median [IQR] age, 52 [47-56] years; 380 female [61.6%]), 223 (36.1%) had a history of TBI. TBI was associated with higher microbleed count (ß = 0.10; 95% CI, 0.01-0.18; P = .03), with a dose-response association observed with increasing number of TBI events (ß = 0.05; 95% CI, 0.01-0.09; P = .03). Conversely, TBI was not associated with other measures of small vessel disease, including WMH. Furthermore, TBI moderated microbleed associations with vascular risk factors and clinical outcomes, such that associations were present only in the absence of TBI. Importantly, observations held when analyses were restricted to individuals reporting only mild TBI. Conclusions and Relevance: In this cross-sectional study of healthy middle-aged adults, detectable changes in brain imaging and clinical features were associated with remote, even mild, TBI in the general population. The potential contribution of vascular injury to TBI-related neurodegeneration presents promising avenues to identify potential targets, with findings highlighting the need to reduce TBI through early intervention and prevention in both clinical care and policymaking.
Subject(s)
Dementia , Neuroimaging , Humans , Female , Middle Aged , Cross-Sectional Studies , Male , Dementia/diagnostic imaging , Neuroimaging/methods , Adult , Magnetic Resonance Imaging/methods , Ireland/epidemiology , United Kingdom/epidemiology , Brain Concussion/diagnostic imaging , Brain Concussion/complications , Risk Factors , Brain Injuries, Traumatic/diagnostic imaging , Brain Injuries, Traumatic/complicationsABSTRACT
How is the information-processing architecture of the human brain organised, and how does its organisation support consciousness? Here, we combine network science and a rigorous information-theoretic notion of synergy to delineate a 'synergistic global workspace', comprising gateway regions that gather synergistic information from specialised modules across the human brain. This information is then integrated within the workspace and widely distributed via broadcaster regions. Through functional MRI analysis, we show that gateway regions of the synergistic workspace correspond to the human brain's default mode network, whereas broadcasters coincide with the executive control network. We find that loss of consciousness due to general anaesthesia or disorders of consciousness corresponds to diminished ability of the synergistic workspace to integrate information, which is restored upon recovery. Thus, loss of consciousness coincides with a breakdown of information integration within the synergistic workspace of the human brain. This work contributes to conceptual and empirical reconciliation between two prominent scientific theories of consciousness, the Global Neuronal Workspace and Integrated Information Theory, while also advancing our understanding of how the human brain supports consciousness through the synergistic integration of information.
The human brain consists of billions of neurons which process sensory inputs, such as sight and sound, and combines them with information already stored in the brain. This integration of information guides our decisions, thoughts, and movements, and is hypothesized to be integral to consciousness. However, it is poorly understood how the brain regions responsible for processing this integration are organized in the brain. To investigate this question, Luppi et al. employed a mathematical framework called Partial Information Decomposition (PID) which can distinguish different types of information: redundancy (available from many regions) and synergy (which reflects genuine integration). The team applied the PID framework to the brain scans of 100 individuals. This allowed them to identify which brain regions combine information from across the brain (known as gateways), and which ones transmit it back to the rest of the brain (known as broadcasters). Next, Luppi et al. set out to find how these regions compared in unconscious and conscious individuals. To do this, they studied 15 healthy volunteers whose brains were scanned (using a technique called functional MRI) before, during, and after anaesthesia. This revealed that the brain integrated less information when unconscious, and that this reduction happens predominantly in gateway rather than broadcaster regions. The same effect was also observed in the brains of individuals who were permanently unconscious due to brain injuries. These findings provide a way of understanding how information is organised in the brain. They also suggest that loss of consciousness due to brain injuries and anaesthesia involve similar brain circuits. This means it may be possible to gain insights about disorders of consciousness from studying how people emerge from anaesthesia.
Subject(s)
Brain , Consciousness , Magnetic Resonance Imaging , Humans , Consciousness/physiology , Brain/physiology , Brain/diagnostic imaging , Male , Adult , Female , Young Adult , Default Mode Network/physiologyABSTRACT
Brain atrophy and cortical thinning are typically observed in people with Alzheimer's disease (AD) and, to a lesser extent, in those with mild cognitive impairment. In asymptomatic middle-aged apolipoprotein ε4 (ΑPOE4) carriers, who are at higher risk of future AD, study reports are discordant with limited evidence of brain structural differences between carriers and non-carriers of the ε4 allele. Alternative imaging markers with higher sensitivity at the presymptomatic stage, ideally quantified using typically acquired structural MRI scans, would thus be of great benefit for the detection of early disease, disease monitoring and subject stratification. In the present cross-sectional study, we investigated textural properties of T1-weighted 3T MRI scans in relation to APOE4 genotype, age and sex. We pooled together data from the PREVENT-Dementia and ALFA studies focused on midlife healthy populations with dementia risk factors (analysable cohort: 1585 participants; mean age 56.2 ± 7.4 years). Voxel-based and texture (examined features: contrast, entropy, energy, homogeneity) based morphometry was used to identify areas of volumetric and textural differences between APOE4 carriers and non-carriers. Textural maps were generated and were subsequently harmonised using voxel-wise COMBAT. For all analyses, APOE4, sex, age and years of education were used as model predictors. Interactions between APOE4 and age were further examined. There were no group differences in regional brain volume or texture based on APOE4 carriership or when age × APOE4 interactions were examined. Older people tended to have a less homogeneous textural profile in grey and white matter and a more homogeneous profile in the ventricles. A more heterogeneous textural profile was observed for females in areas such as the ventricles, frontal and parietal lobes and for males in the brainstem, cerebellum, precuneus and cingulate. Overall, we have shown the absence of volumetric and textural differences between APOE4 carriers and non-carriers at midlife and have established associations of textural features with ageing and sex.
Subject(s)
Aging , Apolipoprotein E4 , Magnetic Resonance Imaging , Adult , Aged , Female , Humans , Male , Middle Aged , Aging/pathology , Aging/genetics , Apolipoprotein E4/genetics , Brain/diagnostic imaging , Brain/pathology , Cross-Sectional Studies , Genotype , Heterozygote , Sex CharacteristicsABSTRACT
PREVENT is a multi-centre prospective cohort study in the UK and Ireland that aims to examine midlife risk factors for dementia and identify and describe the earliest indices of disease development. The PREVENT dementia programme is one of the original epidemiological initiatives targeting midlife as a critical window for intervention in neurodegenerative conditions. This paper provides an overview of the study protocol and presents the first summary results from the initial baseline data to describe the cohort. Participants in the PREVENT cohort provide demographic data, biological samples (blood, saliva, urine and optional cerebrospinal fluid), lifestyle and psychological questionnaires, undergo a comprehensive cognitive test battery and are imaged using multi-modal 3-T MRI scanning, with both structural and functional sequences. The PREVENT cohort governance structure is described, which includes a steering committee, a scientific advisory board and core patient and public involvement groups. A number of sub-studies that supplement the main PREVENT cohort are also described. The PREVENT cohort baseline data include 700 participants recruited between 2014 and 2020 across five sites in the UK and Ireland (Cambridge, Dublin, Edinburgh, London and Oxford). At baseline, participants had a mean age of 51.2 years (range 40-59, SD ± 5.47), with the majority female (n = 433, 61.9%). There was a near equal distribution of participants with and without a parental history of dementia (51.4% versus 48.6%) and a relatively high prevalence of APOEÉ4 carriers (n = 264, 38.0%). Participants were highly educated (16.7 ± 3.44 years of education), were mainly of European Ancestry (n = 672, 95.9%) and were cognitively healthy as measured by the Addenbrookes Cognitive Examination-III (total score 95.6 ± 4.06). Mean white matter hyperintensity volume at recruitment was 2.26 ± 2.77â ml (median = 1.39â ml), with hippocampal volume being 8.15 ± 0.79â ml. There was good representation of known dementia risk factors in the cohort. The PREVENT cohort offers a novel data set to explore midlife risk factors and early signs of neurodegenerative disease. Data are available open access at no cost via the Alzheimer's Disease Data Initiative platform and Dementia Platforms UK platform pending approval of the data access request from the PREVENT steering group committee.
ABSTRACT
Functional interactions between brain regions can be viewed as a network, enabling neuroscientists to investigate brain function through network science. Here, we systematically evaluate 768 data-processing pipelines for network reconstruction from resting-state functional MRI, evaluating the effect of brain parcellation, connectivity definition, and global signal regression. Our criteria seek pipelines that minimise motion confounds and spurious test-retest discrepancies of network topology, while being sensitive to both inter-subject differences and experimental effects of interest. We reveal vast and systematic variability across pipelines' suitability for functional connectomics. Inappropriate choice of data-processing pipeline can produce results that are not only misleading, but systematically so, with the majority of pipelines failing at least one criterion. However, a set of optimal pipelines consistently satisfy all criteria across different datasets, spanning minutes, weeks, and months. We provide a full breakdown of each pipeline's performance across criteria and datasets, to inform future best practices in functional connectomics.
Subject(s)
Brain , Connectome , Magnetic Resonance Imaging , Humans , Magnetic Resonance Imaging/methods , Connectome/methods , Brain/diagnostic imaging , Brain/physiology , Image Processing, Computer-Assisted/methods , Male , Adult , Female , Nerve Net/physiology , Nerve Net/diagnostic imaging , Brain Mapping/methods , Young AdultABSTRACT
Changes in the brain's physiology in Alzheimer's disease are thought to occur early in the disease's trajectory. In this study our aim was to investigate the brain's neurochemical profile in a midlife cohort in relation to risk factors for future dementia using single voxel proton magnetic resonance spectroscopy. Participants in the multi-site PREVENT-Dementia study (age range 40-59 year old) underwent 3T magnetic resonance spectroscopy with the spectroscopy voxel placed in the posterior cingulate/precuneus region. Using LCModel, we quantified the absolute concentrations of myo-inositol, total N-acetylaspartate, total creatine, choline, glutathione and glutamate-glutamine for 406 participants (mean age 51.1; 65.3% female). Underlying partial volume effects were accounted for by applying a correction for the presence of cerebrospinal fluid in the magnetic resonance spectroscopy voxel. We investigated how metabolite concentrations related to apolipoprotein É4 genotype, dementia family history, a risk score (Cardiovascular Risk Factors, Aging and Incidence of Dementia -CAIDE) for future dementia including non-modifiable and potentially-modifiable factors and dietary patterns (adherence to Mediterranean diet). Dementia family history was associated with decreased total N-acetylaspartate and no differences were found between apolipoprotein É4 carriers and non-carriers. A higher Cardiovascular Risk Factors, Aging, and Incidence of Dementia score related to higher myo-inositol, choline, total creatine and glutamate-glutamine, an effect which was mainly driven by older age and a higher body mass index. Greater adherence to the Mediterranean diet was associated with lower choline, myo-inositol and total creatine; these effects did not survive correction for multiple comparisons. The observed associations suggest that at midlife the brain demonstrates subtle neurochemical changes in relation to both inherited and potentially modifiable risk factors for future dementia.
ABSTRACT
INTRODUCTION: While Latin America (LatAm) is facing an increasing burden of dementia due to the rapid aging of the population, it remains underrepresented in dementia research, diagnostics, and care. METHODS: In 2023, the Alzheimer's Association hosted its eighth satellite symposium in Mexico, highlighting emerging dementia research, priorities, and challenges within LatAm. RESULTS: Significant initiatives in the region, including intracountry support, showcased their efforts in fostering national and international collaborations; genetic studies unveiled the unique genetic admixture in LatAm; researchers conducting emerging clinical trials discussed ongoing culturally specific interventions; and the urgent need to harmonize practices and studies, improve diagnosis and care, and use affordable biomarkers in the region was highlighted. DISCUSSION: The myriad of topics discussed at the 2023 AAIC satellite symposium highlighted the growing research efforts in LatAm, providing valuable insights into dementia biology, genetics, epidemiology, treatment, and care.
Subject(s)
Dementia , Humans , Dementia/therapy , Dementia/diagnosis , Dementia/genetics , Dementia/epidemiology , Latin America/epidemiology , Mexico/epidemiology , Alzheimer Disease/therapy , Alzheimer Disease/diagnosis , Alzheimer Disease/genetics , Biomedical Research , Congresses as TopicABSTRACT
A reduction in the volume of the thalamus and its nuclei has been reported in Alzheimer's disease, mild cognitive impairment and asymptomatic individuals with risk factors for early-onset Alzheimer's disease. Some studies have reported thalamic atrophy to occur prior to hippocampal atrophy, suggesting thalamic pathology may be an early sign of cognitive decline. We aimed to investigate volumetric differences in thalamic nuclei in middle-aged, cognitively unimpaired people with respect to dementia family history and apolipoprotein ε4 allele carriership and the relationship with cognition. Seven hundred participants aged 40-59 years were recruited into the PREVENT Dementia study. Individuals were stratified according to dementia risk (approximately half with and without parental dementia history). The subnuclei of the thalamus of 645 participants were segmented on T1-weighted 3â T MRI scans using FreeSurfer 7.1.0. Thalamic nuclei were grouped into six regions: (i) anterior, (ii) lateral, (iii) ventral, (iv) intralaminar, (v) medial and (vi) posterior. Cognitive performance was evaluated using the computerized assessment of the information-processing battery. Robust linear regression was used to analyse differences in thalamic nuclei volumes and their association with cognitive performance, with age, sex, total intracranial volume and years of education as covariates and false discovery rate correction for multiple comparisons. We did not find significant volumetric differences in the thalamus or its subregions, which survived false discovery rate correction, with respect to first-degree family history of dementia or apolipoprotein ε4 allele status. Greater age was associated with smaller volumes of thalamic subregions, except for the medial thalamus, but only in those without a dementia family history. A larger volume of the mediodorsal medial nucleus (Pfalse discovery rate = 0.019) was associated with a faster processing speed in those without a dementia family history. Larger volumes of the thalamus (P = 0.016) and posterior thalamus (Pfalse discovery rate = 0.022) were associated with significantly worse performance in the immediate recall test in apolipoprotein ε4 allele carriers. We did not find significant volumetric differences in thalamic subregions in relation to dementia risk but did identify an interaction between dementia family history and age. Larger medial thalamic nuclei may exert a protective effect on cognitive performance in individuals without a dementia family history but have little effect on those with a dementia family history. Larger volumes of posterior thalamic nuclei were associated with worse recall in apolipoprotein ε4 carriers. Our results could represent initial dysregulation in the disease process; further study is needed with functional imaging and longitudinal analysis.
ABSTRACT
The apolipoprotein E É4 allele is the primary genetic risk factor for the sporadic type of Alzheimer's disease. However, the mechanisms by which apolipoprotein E É4 are associated with neurodegeneration are still poorly understood. We applied the Neurite Orientation Dispersion Model to characterize the effects of apolipoprotein É4 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 É4 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 É4, and (ii) the interactions of apolipoprotein E É4 with age and education on lobar and vertex-wise Orientation Dispersion Index and implemented using Permutation Analysis of Linear Models. There were apolipoprotein E É4 × age interactions in the temporo-parietal and frontal lobes, indicating steeper age-dependent Orientation Dispersion Index changes in apolipoprotein E É4 carriers. Steeper age-related Orientation Dispersion Index declines were observed among apolipoprotein E É4 carriers with lower years of education. We demonstrated that apolipoprotein E É4 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 É4 may hasten the onset age of dementia by accelerating age-dependent reductions in cortical Orientation Dispersion Index.
ABSTRACT
To date, there is a considerable heterogeneity of methods to score Allostatic Load (AL). Here we propose a comprehensive algorithm (ALCS) that integrates commonly used approaches to generate AL risk categories and assess associations to brain structure deterioration. In a cohort of cognitively normal mid-life adults (n = 620, age 51.3 ± 5.48 years), we developed a comprehensive composite for AL scoring incorporating gender and age differences, high quartile approach, clinical reference values, and current medications, to then generate AL risk categories. Compared to the empirical approach (ALES), ALCS showed better model fit criteria and a strong association with age and sex. ALSC categories were regressed against brain and white matter hyperintensity (WMH) volumes. Higher AL risk categories were associated with increased total, periventricular, frontal, and left parietal WMH volumes, also showing better fit compared to ALES. When cardiovascular biomarkers were removed from the ALSC algorithm, only left-frontal WMHV remained associated with AL, revealing a strong vascular burden influencing the index. Our results agree with previous evidence and suggest that sustained stress exposure enhances brain deterioration in mid-life adults. Showing better fit than ALES, our comprehensive algorithm can provide a more accurate AL estimation to explore how stress exposure enhances age-related health decline.
Subject(s)
Allostasis , White Matter , Adult , Humans , Middle Aged , White Matter/diagnostic imaging , Brain , Magnetic Resonance ImagingABSTRACT
It has been suggested that conscious experience is linked to the richness of brain state repertories, which change in response to environmental and internal stimuli. High-level sensory stimulation has been shown to alter local brain activity and induce neural synchrony across participants. However, the dynamic interplay of cognitive processes underlying moment-to-moment information processing remains poorly understood. Using naturalistic movies as an ecological laboratory model of the real world, here we investigate how the processing of complex naturalistic stimuli alters the dynamics of brain network interactions and how these in turn support information processing. Participants underwent fMRI recordings during movie watching, scrambled movie watching, and resting. By measuring the phase-synchrony between different brain networks, we analyzed whole-brain connectivity patterns. Our finding revealed distinct connectivity patterns associated with each experimental condition. We found higher synchronization of brain patterns across participants during movie watching compared to rest and scrambled movie conditions. Furthermore, synchronization levels increased during the most engaging parts of the movie. The synchronization dynamics among participants were associated with suspense; scenes with higher levels of suspense induced greater synchronization. These results suggest that processing the same high-level information elicits common neural dynamics across individuals, and that whole-brain functional connectivity tracks variations in processed information and subjective experience.
Subject(s)
Brain , Cognition , Humans , Brain/diagnostic imaging , Brain/physiology , Brain Mapping/methods , Magnetic Resonance Imaging/methods , Consciousness , Motion PicturesABSTRACT
The human brain is characterised by idiosyncratic patterns of spontaneous thought, rendering each brain uniquely identifiable from its neural activity. However, deep general anaesthesia suppresses subjective experience. Does it also suppress what makes each brain unique? Here we used functional MRI under the effects of the general anaesthetics sevoflurane and propofol to determine whether anaesthetic-induced unconsciousness diminishes the uniqueness of the human brain: both with respect to the brains of other individuals, and the brains of another species. We report that under anaesthesia individual brains become less self-similar and less distinguishable from each other. Loss of distinctiveness is highly organised: it co-localises with the archetypal sensory-association axis, correlating with genetic and morphometric markers of phylogenetic differences between humans and other primates. This effect is more evident at greater anaesthetic depths, reproducible across sevoflurane and propofol, and reversed upon recovery. Providing convergent evidence, we show that under anaesthesia the functional connectivity of the human brain becomes more similar to the macaque brain. Finally, anaesthesia diminishes the match between spontaneous brain activity and meta-analytic brain patterns aggregated from the NeuroSynth engine. Collectively, the present results reveal that anaesthetised human brains are not only less distinguishable from each other, but also less distinguishable from the brains of other primates, with specifically human-expanded regions being the most affected by anaesthesia.
ABSTRACT
Although each of us was once a baby, infant consciousness remains mysterious and there is no received view about when, and in what form, consciousness first emerges. Some theorists defend a 'late-onset' view, suggesting that consciousness requires cognitive capacities which are unlikely to be in place before the child's first birthday at the very earliest. Other theorists defend an 'early-onset' account, suggesting that consciousness is likely to be in place at birth (or shortly after) and may even arise during the third trimester. Progress in this field has been difficult, not just because of the challenges associated with procuring the relevant behavioral and neural data, but also because of uncertainty about how best to study consciousness in the absence of the capacity for verbal report or intentional behavior. This review examines both the empirical and methodological progress in this field, arguing that recent research points in favor of early-onset accounts of the emergence of consciousness.
Subject(s)
Consciousness , Infant, Newborn , Child , Infant , Humans , UncertaintyABSTRACT
Integrated Information Theory was developed to explain and quantify consciousness, arguing that conscious systems consist of elements that are integrated through their causal properties. This study presents an implementation of Integrated Information Theory 3.0, the latest version of this framework, to functional MRI data. Data were acquired from 17 healthy subjects who underwent sedation with propofol, a short-acting anaesthetic. Using the PyPhi software package, we systematically analyze how Φmax, a measure of integrated information, is modulated by the sedative in different resting-state networks. We compare Φmax to other proposed measures of conscious level, including the previous version of integrated information, Granger causality, and correlation-based functional connectivity. Our results indicate that Φmax presents a variety of sedative-induced behaviours for different networks. Notably, changes to Φmax closely reflect changes to subjects' conscious level in the frontoparietal and dorsal attention networks, which are responsible for higher-order cognitive functions. In conclusion, our findings present important insight into different measures of conscious level that will be useful in future implementations to functional MRI and other forms of neuroimaging.
Subject(s)
Magnetic Resonance Imaging , Propofol , Humans , Magnetic Resonance Imaging/methods , Information Theory , Consciousness , Hypnotics and SedativesABSTRACT
To understand how pharmacological interventions can exert their powerful effects on brain function, we need to understand how they engage the brain's rich neurotransmitter landscape. Here, we bridge microscale molecular chemoarchitecture and pharmacologically induced macroscale functional reorganization, by relating the regional distribution of 19 neurotransmitter receptors and transporters obtained from positron emission tomography, and the regional changes in functional magnetic resonance imaging connectivity induced by 10 different mind-altering drugs: propofol, sevoflurane, ketamine, lysergic acid diethylamide (LSD), psilocybin, N,N-Dimethyltryptamine (DMT), ayahuasca, 3,4-methylenedioxymethamphetamine (MDMA), modafinil, and methylphenidate. Our results reveal a many-to-many mapping between psychoactive drugs' effects on brain function and multiple neurotransmitter systems. The effects of both anesthetics and psychedelics on brain function are organized along hierarchical gradients of brain structure and function. Last, we show that regional co-susceptibility to pharmacological interventions recapitulates co-susceptibility to disorder-induced structural alterations. Collectively, these results highlight rich statistical patterns relating molecular chemoarchitecture and drug-induced reorganization of the brain's functional architecture.
Subject(s)
Ketamine , Methylphenidate , Humans , Brain , Membrane Transport Proteins , ModafinilABSTRACT
Cerebral hemodynamic alterations have been observed in apolipoprotein ε4 (APOE4) carriers at midlife, however the physiological underpinnings of this observation are poorly understood. Our goal was to investigate cerebral blood flow (CBF) and its spatial coefficient of variation (CoV) in relation to APOE4 and a measure of erythrocyte anisocytosis (red blood cell distribution width - RDW) in a middle-aged cohort. Data from 563 participants in the PREVENT-Dementia study scanned with 3 T MRI cross-sectionally were analysed. Voxel-wise and region-of-interest analyses within nine vascular regions were run to detect areas of altered perfusion. Within the vascular regions, interaction terms between APOE4 and RDW in predicting CBF were examined. Areas of hyperperfusion in APOE4 carriers were detected mainly in frontotemporal regions. The APOE4 allele differentially moderated the association between RDW and CBF, an association which was more prominent in the distal vascular territories (p - [0.01, 0.05]). The CoV was not different between the considered groups. We provide novel evidence that in midlife, RDW and CBF are differentially associated in APOE4 carriers and non-carriers. This association is consistent with a differential hemodynamic response to hematological alterations in APOE4 carriers.
Subject(s)
Alzheimer Disease , Apolipoprotein E4 , Cerebrovascular Circulation , Erythrocyte Indices , Humans , Middle Aged , Age Factors , Alzheimer Disease/genetics , Apolipoprotein E4/genetics , Cerebrovascular Circulation/genetics , Erythrocyte Indices/genetics , HeterozygoteABSTRACT
Anaesthesia combined with functional neuroimaging provides a powerful approach for understanding the brain mechanisms of consciousness. Although propofol is used ubiquitously in clinical interventions that reversibly suppress consciousness, it shows large inter-individual variability, and the brain bases of this variability remain poorly understood. We asked whether three networks key to conscious cognition-the dorsal attention (DAN), executive control (ECN), and default mode (DMN)-underlie responsiveness variability under anaesthesia. Healthy participants (N = 17) were moderately anaesthetized during narrative understanding and resting-state conditions inside the Magnetic Resonance Imaging scanner. A target detection task measured behavioural responsiveness. An independent behavioural study (N = 25) qualified the attention demands of narrative understanding. Then, 30% of participants were unaffected in their response times, thus thwarting a key aim of anaesthesia-the suppression of behavioural responsiveness. Individuals with stronger functional connectivity within the DAN and ECN, between them, and to the DMN, and with larger grey matter volume in frontal regions were more resilient to anaesthesia. For the first time, we show that responsiveness variability during propofol anaesthesia relates to inherent differences in brain structure and function of the frontoparietal networks, which can be predicted prior to sedation. Results highlight novel markers for improving awareness monitoring during clinical anaesthesia.
Subject(s)
Anesthesia , Propofol , Humans , Propofol/pharmacology , Brain/diagnostic imaging , Brain/physiology , Consciousness/physiology , Cognition , Brain Mapping , Magnetic Resonance Imaging/methods , Neural Pathways/diagnostic imaging , Executive FunctionABSTRACT
BACKGROUND: It is now acknowledged that Alzheimer's disease (AD) processes are present decades before the onset of clinical symptoms, but it remains unknown whether lifestyle factors can protect against these early AD processes in mid-life. OBJECTIVE: We asked whether modifiable lifestyle activities impact cognition in middle-aged individuals who are cognitively healthy, but at risk for late life AD. Participants (40-59 years) completed cognitive and clinical assessments at baseline (Nâ=â206) and two years follow-up (Nâ=â174). METHODS: Mid-life activities were measured with the Lifetime of Experiences Questionnaire. We assessed the impact of lifestyle activities, known risk factors for sporadic late-onset AD (Apolipoprotein E É4 allele status, family history of dementia, and the Cardiovascular Risk Factors Aging and Dementia score), and their interactions on cognition. RESULTS: More frequent engagement in physically, socially, and intellectually stimulating activities was associated with better cognition (verbal, spatial, and relational memory), at baseline and follow-up. Critically, more frequent engagement in these activities was associated with stronger cognition (verbal and visuospatial functions, and conjunctive short-term memory binding) in individuals with family history of dementia. Impaired visuospatial function is one of the earliest cognitive deficits in AD and has previously associated with increased AD risk in this cohort. Additionally, conjunctive memory functions have been found impaired in the pre-symptomatic stages of AD. CONCLUSION: These findings suggest that modifiable lifestyle activities offset cognitive decrements due to AD risk in mid-life and support the targeting of modifiable lifestyle activities for the prevention of AD.