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Background We aimed to investigate the association between OA and treatment with dementia risk and structural brain abnormalities. Methods We recruited a total of 466,460 individuals from the UK Biobank to investigate the impact of OA on the incidence of dementia. Among the total population, there were 63,081 participants diagnosed with OA. We subsequently categorised the OA patients into medication and surgery groups based on treatment routes. Cox regression models explored the associations between OA/OA treatment and dementia risk, with the results represented as hazard ratios (HRs) and 95% confidence intervals (95% CI). Linear regression models assessed the associations of OA/OA therapy with alterations in cortical structure. Results During an average of 11.90 (± 1.01) years of follow-up, 5,627 individuals were diagnosed with all-cause dementia (ACD), including 2,438 AD (Alzheimer's disease), and 1,312 VaD (vascular dementia) cases. Results revealed that OA was associated with the elevated risk of ACD (HR: 1.116; 95% CI: 1.039–1.199) and AD (HR: 1.127; 95% CI: 1.013–1.254). OA therapy lowered the risk of dementia in both medication group (HR: 0.746; 95% CI: 0.652–0.854) and surgery group (HR: 0.841; 95% CI: 0.736–0.960). OA was negatively associated with cortical area, especially precentral, postcentral and temporal regions. Conclusions Osteoarthritis increased the likelihood of developing dementia, and had an association with regional brain atrophy. OA treatment lowered the dementia risk. OA is a promising modifiable risk factor for dementia. [ABSTRACT FROM AUTHOR]

Parenthood, particularly motherhood, is known to impact the structure and function of the brain in the short term, but the long-term effects of parenthood and their impacts on well-being are still poorly understood. This study explores the potential longer-term associations between parenthood and the brain, parenthood and well-being, and the potential role of brain modifications in influencing mothers' well-being. Using data from the UK Biobank, which includes brain imaging information from individuals aged 45–82 at the MRI scanning, we discovered differences in brain structure between mothers and non-mothers, with mothers exhibiting widely distributed higher gray matter density, particularly strong in frontal and occipital regions. No brain changes were observed in fathers. Parents reported a higher sense of life's meaning compared to their childless counterparts. Gray matter changes did not mediate the relationship between motherhood and well-being. This suggests that the alterations in gray matter associated with motherhood do not play a deterministic role in shaping long-term changes in well-being. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) has been associated with alterations in the brain cortical structure. Nonetheless, the causality between COPD and brain cortical structure has not been determined. In the present study, we used Mendelian randomization (MR) analysis to explore the causal effects of genetic predicated COPD on brain cortical structure, namely cortical surface area (SA) and cortical thickness (TH). Genetic association summary data for COPD were obtained from the FinnGen consortium (N = 358,369; Ncase = 20,066). PRISm summary genetic data were retrieved from a case–control GWAS conducted in the UK Biobank (N = 296,282). Lung function indices, including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC, were extracted from a meta-analysis of the UK Biobank and SpiroMeta consortium (N = 400,102). Brain cortical structure data were obtained from the ENIGMA consortium (N = 51,665). Inverse-variance weighted (IVW) method was used as the primary analysis, and a series of sensitivity tests were exploited to evaluate the heterogeneity and pleiotropy of our results. The results identified potential causal effects of COPD on several brain cortical specifications, including pars orbitalis, cuneus and inferior parietal gyrus. Furthermore, genetic predicated lung function index (FEV1, FVC and FEV1/FVC), as well as PRISm, also has causal effects on brain cortical structure. According to our results, a total of 15 functional specifications were influenced by lung function index and PRISm. These findings contribute to understanding the causal effects of COPD and lung function to brain cortical structure. [ABSTRACT FROM AUTHOR]

Aim: Knowledge of how circadian rhythm influences brain health remains limited. We aimed to investigate the associations of accelerometer‐measured circadian rest‐activity rhythm (CRAR) with incident dementia, cognitive dysfunction, and structural brain abnormalities in the general population and underlying biological mechanisms. Methods: Fifty‐seven thousand five hundred and two participants aged over 60 years with accelerometer data were included to investigate the association of CRAR with incidental dementia. Non‐parametric CRAR parameters were utilized, including activity level during active periods of the day (M10), activity level during rest periods of the day (L5), and the relative difference between the M10 and L5 (relative amplitude, RA). Associations of CRAR with cognitive dysfunction and brain structure were studied in a subset of participants. Neuroimaging‐transcriptomics analysis was utilized to identify the underlying molecular mechanisms. Results: Over 6.86 (4.94–8.78) years of follow‐up, 494 participants developed dementia. The risk of incident dementia was associated with decreasing M10 (hazard ratio [HR] 1.45; 95% conference interval [CI], 1.28–1.64) and RA (HR 1.37; 95% CI, 1.28–1.64), increasing L5 (HR 1.14, 95% CI 1.07–1.21) and advanced L5 onset time (HR 1.12; 95% CI, 1.02–1.23). The detrimental associations were exacerbated by APOE ε4 status and age (>65 years). Decreased RA was associated with lower processing speed (Beta −0.04; SE 0.011), predominantly mediated by abnormalities in subcortical regions and white matter microstructure. The genes underlying CRAR‐related brain regional structure variation were enriched for synaptic function. Conclusions: Our study underscores the potential of intervention targeting at maintaining a healthy CRAR pattern to prevent dementia risk. [ABSTRACT FROM AUTHOR]

Background: Computer gaming has recently been suggested to be associated with benefits for cognition, but its impact on incident dementia remains uncertain. We aimed to investigate the observational associations of playing computer games with incident dementia, cognitive functions, and brain structural measures, and further explore the genetic associations between computer gaming and dementia. Methods: We included 471,346 White British participants without dementia at baseline based on the UK Biobank, and followed them until November 2022. We estimated the risk of dementia using Cox proportional hazard models, and assessed the changes of cognitive functions and brain structural measures using logistic regression models and linear regression models. Mendelian randomization (MR) analyses were performed to examine the association between genetically determined computer gaming and dementia. Results: High frequency of playing computer games was associated with decreased risk of incident dementia (HR, 0.81 [95% CI: 0.69, 0.94]). Individuals with high frequency of playing computer games had better performance in prospective memory (OR, 1.46 [1.26, 1.70]), reaction time (beta, -0.195 [-0.243, -0.147]), fluid intelligence (0.334 [0.286, 0.382]), numeric memory (0.107 [0.047, 0.166]), incorrect pairs matching (-0.253 [-0.302, -0.203]), and high volume of gray matter in hippocampus (0.078 [0.023, 0.134]). Genetically determined high frequency of playing computer games was associated with a low risk of dementia (OR, 0.37 [0.15, 0.91]). Conclusions: Computer gaming was associated with a decreased risk of dementia, favorable cognitive function, and better brain structure, suggesting that computer gaming could modulate cognitive function and may be a promising target for dementia prevention. [ABSTRACT FROM AUTHOR]

Physical activity is a protective factor against brain atrophy, while loss of brain volume could also be a determinant of physical activity. Therefore, we aimed to explore the bidirectional association of physical activity with brain structures in middle-aged and older adults from the UK Biobank. Overall, 3027 participants (62.45 ± 7.27 years old, 51.3% females) had data at two time points. Hippocampal volume was associated with total (β=0.048, p FDR =0.016) and household (β=0.075, p FDR <0.001) physical activity. Global fractional anisotropy (β=0.042, p FDR =0.028) was also associated with household physical activity. In the opposite direction, walking was negatively associated with white matter volume (β=-0.026, p FDR =0.008). All these associations were confirmed by the linear mixed models. Interestingly, sports at baseline were linked to hippocampal and frontal cortex volumes at follow-up but these associations disappeared after adjusting for multiple comparisons (p all >0.104). In conclusion, we found more consistent evidence that a healthier brain structure predicted higher physical activity levels than for the inverse, more established relationship. • The association between brain structure and physical activity seems more consistent. • Hippocampal, and global fractional anisotropy linked to housework at follow-up. • Sports were borderline linked to hippocampal and frontal volumes at follow-up. [ABSTRACT FROM AUTHOR]

Cross-sectional studies have demonstrated strong associations between physical frailty and depression. However, the evidence from prospective studies is limited. Here, we analyze data of 352,277 participants from UK Biobank with 12.25-year follow-up. Compared with non-frail individuals, pre-frail and frail individuals have increased risk for incident depression independent of many putative confounds. Altogether, pre-frail and frail individuals account for 20.58% and 13.16% of depression cases by population attributable fraction analyses. Higher risks are observed in males and individuals younger than 65 years than their counterparts. Mendelian randomization analyses support a potential causal effect of frailty on depression. Associations are also observed between inflammatory markers, brain volumes, and incident depression. Moreover, these regional brain volumes and three inflammatory markers—C-reactive protein, neutrophils, and leukocytes—significantly mediate associations between frailty and depression. Given the scarcity of curative treatment for depression and the high disease burden, identifying potential modifiable risk factors of depression, such as frailty, is needed. Identifying modifiable risk factors that could prevent depression is important. Here, the authors show increased risks of incident depression in pre-frail and frail individuals and highlight the mediating role of brain structure and inflammation. [ABSTRACT FROM AUTHOR]

Childhood maltreatment (CM) leads to a lifelong susceptibility to mental ill-health which might be reflected by its effects on adult brain structure, perhaps indirectly mediated by its effects on adult metabolic, immune, and psychosocial systems. Indexing these systemic factors via body mass index (BMI), C-reactive protein (CRP), and rates of adult trauma (AT), respectively, we tested three hypotheses: (H1) CM has direct or indirect effects on adult trauma, BMI, and CRP; (H2) adult trauma, BMI, and CRP are all independently related to adult brain structure; and (H3) childhood maltreatment has indirect effects on adult brain structure mediated in parallel by BMI, CRP, and AT. Using path analysis and data from N = 116,887 participants in UK Biobank, we find that CM is related to greater BMI and AT levels, and that these two variables mediate CM's effects on CRP [H1]. Regression analyses on the UKB MRI subsample (N = 21,738) revealed that greater CRP and BMI were both independently related to a spatially convergent pattern of cortical effects (Spearman's ρ = 0.87) characterized by fronto-occipital increases and temporo-parietal reductions in thickness. Subcortically, BMI was associated with greater volume, AT with lower volume and CPR with effects in both directions [H2]. Finally, path models indicated that CM has indirect effects in a subset of brain regions mediated through its direct effects on BMI and AT and indirect effects on CRP [H3]. Results provide evidence that childhood maltreatment can influence brain structure decades after exposure by increasing individual risk toward adult trauma, obesity, and inflammation. [ABSTRACT FROM AUTHOR]

To gain insights into the role of brain structure and function on anxiety (ANX), we conducted a genetically informed investigation leveraging information from ANX genome-wide association studies available from the UK Biobank (n = 380,379), the FinnGen Program (n = 290,361), and the Million Veteran Program (n = 175,163) together with UK Biobank genome-wide data (n = 33,224) related to 3935 brain imaging–derived phenotypes (IDPs). A genetic correlation analysis between ANX and brain IDPs was performed using linkage disequilibrium score regression. To investigate ANX–brain associations, a 2-sample Mendelian randomization was performed considering multiple methods and sensitivity analyses. A subsequent multivariable Mendelian randomization was conducted to distinguish between direct and indirect effects. Finally, a generalized linear model was used to explore the associations of brain IDPs with ANX symptoms. After false discovery rate correction (q <.05), we identified 41 brain IDPs genetically correlated with ANX without heterogeneity among the datasets investigated (i.e., UK Biobank, FinnGen, and Million Veteran Program). Six of these IDPs showed genetically inferred causal effects on ANX. In the subsequent multivariable Mendelian randomization analysis, reduced area of the right posterior middle cingulate gyrus (β = −0.09, p = 8.01 × 10−4) and reduced gray matter volume of the right anterior superior temporal gyrus (β = −0.09, p = 1.55 × 10−3) had direct effects on ANX. In the ANX symptom-level analysis, the right posterior middle cingulate gyrus was negatively associated with "tense, sore, or aching muscles during the worst period of anxiety" (β = −0.13, p = 8.26 × 10−6). This study identified genetically inferred effects that are generalizable across large cohorts, thereby contributing to our understanding of how changes in brain structure and function can lead to ANX. [ABSTRACT FROM AUTHOR]

Understanding the genetic architecture of brain structure is challenging, partly due to difficulties in designing robust, non-biased descriptors of brain morphology. Until recently, brain measures for genome-wide association studies (GWAS) consisted of traditionally expert-defined or software-derived image-derived phenotypes (IDPs) that are often based on theoretical preconceptions or computed from limited amounts of data. Here, we present an approach to derive brain imaging phenotypes using unsupervised deep representation learning. We train a 3-D convolutional autoencoder model with reconstruction loss on 6130 UK Biobank (UKBB) participants' T1 or T2-FLAIR (T2) brain MRIs to create a 128-dimensional representation known as Unsupervised Deep learning derived Imaging Phenotypes (UDIPs). GWAS of these UDIPs in held-out UKBB subjects (n = 22,880 discovery and n = 12,359/11,265 replication cohorts for T1/T2) identified 9457 significant SNPs organized into 97 independent genetic loci of which 60 loci were replicated. Twenty-six loci were not reported in earlier T1 and T2 IDP-based UK Biobank GWAS. We developed a perturbation-based decoder interpretation approach to show that these loci are associated with UDIPs mapped to multiple relevant brain regions. Our results established unsupervised deep learning can derive robust, unbiased, heritable, and interpretable brain imaging phenotypes. A study utilizing unsupervised deep learning to generate interpretable brain imaging phenotypes from brain T1 and T2-FLAIR MRI identified 97 genetic loci enhancing understanding of brain structure genetics. [ABSTRACT FROM AUTHOR]

Previous researchers have tried to explore the association between folate/folic acid intake and dementia incidence, but the results remain controversial. We evaluated the associations of folate/folic acid supplementation alone and in combination with other B vitamins on dementia risk and brain structure. A total of 466 224 UK Biobank participants were investigated. Cox proportional hazards models were used to assess the associations between folate/folic acid supplementation status and the risk of Alzheimer's disease (AD) and vascular dementia (VD). Multivariable linear regression models were employed to evaluate the association between folate/folic acid supplementation status and brain structure. In the final model, folate/folic acid supplementation alone was significantly associated with a higher risk of AD (hazard ratio [HR] = 1.34, 95% confidence interval [CI] = 1.06–1.69, p  = .015) and VD (HR = 1.61, 95% CI = 1.21–2.13, p  = .001). Folate/folic acid supplementation alone was associated with a reduction in the hippocampus (β = −95.25 mm3, 95% CI = −165.31 to −25.19 mm3, p  = .014) and amygdala (β = −51.85 mm3, 95% CI = −88.02 to −15.68 mm3, p  = .012). The risk of AD and VD, as well as brain structure, in the group with combined folate/folic acid supplementation and other B vitamins did not show a statistically significant difference compared to the reference group (all p  > .05). Folate/folic acid supplementation alone is significantly associated with a higher risk of AD and VD, as well as adverse alterations in brain structure. However, when combined with other B vitamins, these detrimental effects can be counteracted. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The presence of multiple cardiometabolic diseases (CMDs) has been linked to increased dementia risk, but the combined influence of CMDs on cognition and brain structure across the life course is unclear. METHODS: In the UK Biobank, 46,562 dementia‐free participants completed a cognitive test battery at baseline and a follow‐up visit 9 years later, at which point 39,306 also underwent brain magnetic resonance imaging. CMDs (diabetes, heart disease, and stroke) were ascertained from medical records. Data were analyzed using age‐stratified (middle age [< 60] versus older [≥ 60]) mixed‐effects models and linear regression. RESULTS: A higher number of CMDs was associated with significantly steeper global cognitive decline in older (β = –0.008; 95% confidence interval: −0.012, −0.005) but not middle age. Additionally, the presence of multiple CMDs was related to smaller total brain volume, gray matter volume, white matter volume, and hippocampal volume and larger white matter hyperintensity volume, even in middle age. DISCUSSION: CMDs are associated with cognitive decline in older age and poorer brain structural health beginning already in middle age. Highlights: We explored the association of CMDs with cognitive decline and brain MRI measures.CMDs accelerated cognitive decline in older (≥60y) but not middle (<60) age.CMDs were associated with poorer brain MRI parameters in both middle and older age.Results highlight the connection between CMDs and cognitive/brain aging. [ABSTRACT FROM AUTHOR]

Introduction: As individuals age, their sleep patterns change, and sleep disturbances can increase the risk of dementia. Poor sleep quality can be a risk factor for mild cognitive impairment (MCI) and dementia. Epidemiological studies show a connection between sleep quality and cognitive changes, with brain imaging revealing grey matter volume reduction and amyloid beta accumulation in Alzheimer's disease. However, most research has focused on Europeans, with little attention to other ethnic groups. Methods: This is a cross sectional study comparing effects across countries and ethnicities. Group 1 (n = 193) will be Indians residing in India (new participant recruitment), Group 2 will be South Asians residing in UK and group 3 will be Europeans residing in the UK. For group 2 and 3 (n = 193), data already collected by UK-based Southall and Brent REvisited (SABRE) tri-ethnic study will be used. For group 1, Pittsburgh Sleep Quality Index questionnaire (PSQI) will be used for assessment of sleep quality, Indian Council of Medical Research (Neurocognitive ToolBox) (ICMR-NCTB) for cognition testing and a 3 T MRI cerebral scan for brain morphometry. The data will be compared to sleep, cognitive function and brain MRI parameters from SABRE. Discussion: Racial and ethnic differences can impact the relationships of cognitive function, sleep quality and brain structure in older adults. Earlier studies have highlighted higher prevalence of poor sleep among black individuals compared to white individuals. Genetic or epigenetic mechanisms may contribute to these variations. Socio-cultural and environmental factors, such as neighbourhood, migration, lifestyle, stress and perceived discrimination may influence sleep patterns. The aim of the study is to examine the ethnogeographic variations in sleep quality, cognitive performance and brain morphometry among Indians living in India, and South Asians and Europeans residing in the UK. [ABSTRACT FROM AUTHOR]

Chronic pain affects nearly 20% of the U.S. population. It is a leading cause of disability globally and is associated with a heightened risk for suicide. The role of the central nervous system in the perception and maintenance of chronic pain has recently been accepted, but specific brain circuitries involved have yet to be mapped across pain types in a large-scale study. We used data from the UK Biobank (N = 21,968) to investigate brain structural alterations in individuals reporting chronic pain compared with pain-free control participants and their mediating effect on history of suicide attempt. Chronic pain and, more notably, chronic multisite pain was associated with, on average, lower surface area throughout the cortex after adjusting for demographic, clinical, and neuropsychiatric confounds. Only participants with abdominal pain showed lower subcortical volumes, including the amygdala and brainstem, and lower cerebellum volumes. Participants with chronic headaches showed a widespread thicker cortex compared with control participants. Mediation analyses revealed that precuneus thickness mediated the relationship of chronic multisite pain and history of suicide attempt. Mediating effects were also identified specific to localized pain, with the strongest effect being amygdala volume in individuals with chronic abdominal pain. Results support a widespread effect of chronic pain on brain structure and distinct brain structures underlying chronic musculoskeletal pain, visceral pain, and headaches. Mediation effects of regions in the extended ventromedial prefrontal cortex subsystem suggest that exacerbated negative internal states, negative self-referencing, and impairments in future planning may underlie suicidal behaviors in individuals with chronic pain. [ABSTRACT FROM AUTHOR]

The relationship between liver dysfunction and dementia has been researched extensively but remains poorly understood. In this study, we investigate the longitudinal and cross‐sectional associations between liver function and liver diseases and risk of incident dementia, impaired cognition, and brain structure abnormalities using Cox proportion hazard model and linear regression model. 431 699 participants with a mean of 8.65 (standard deviation [SD] 2.61) years of follow‐up were included from the UK Biobank; 5542 all‐cause dementia (ACD), 2427 Alzheimer's disease (AD), and 1282 vascular dementia (VaD) cases were documented. We observed that per SD decreases in alanine transaminase (ALT; hazard ratio [HR], 0.917; PFDR <0.001) and per SD increases in aspartate aminotransferase (AST; HR, 1.048; PFDR = 0.010), AST to ALT ratio (HR, 1.195; PFDR <0.001), gamma‐glutamyl transpeptidase (GGT; HR, 1.066; PFDR <0.001), alcoholic liver disease (ALD; HR, 2.872; PFDR <0.001), and fibrosis and cirrhosis of liver (HR, 2.285; PFDR = 0.002), being significantly associated with a higher risk of incident ACD. Restricted cubic spline models identified a strong U‐shaped association between Alb and AST and incident ACD (Pnonlinear <0.05). Worse cognition was positively correlated with AST, AST to ALT ratio, direct bilirubin (DBil), and GGT; negatively correlated with ALT, Alb, and total bilirubin (TBil); and ALD and fibrosis and cirrhosis of liver (PFDR <0.05). Moreover, changes in ALT, GGT, AST to ALT ratio, and ALD were significantly associated with altered cortical and subcortical regions, including hippocampus, amygdala, thalamus, pallidum, and fusiform (PFDR <0.05). In sensitivity analysis, metabolic dysfunction‐associated steatotic liver disease (MASLD) was associated with the risk of ACD and brain subcortical changes. Our findings provide substantial evidence that liver dysfunction may be an important factor for incident dementia. Early intervention in the unhealthy liver may help prevent cognitive impairment and dementia incidence. [ABSTRACT FROM AUTHOR]

For many brain disorders, a subset of patients jointly exhibit alterations in cortical brain structure and elevated levels of circulating immune markers. This may be driven in part by shared genetic architecture. Therefore, we investigated the phenotypic and genetic associations linking global cortical surface area and thickness with blood immune markers (i.e., white blood cell counts and plasma C-reactive protein levels). Linear regression was used to assess phenotypic associations in 30,823 UK Biobank participants. Genome-wide and local genetic correlations were assessed using linkage disequilibrium score regression and local analysis of covariance annotation. The number of shared trait-influencing genetic variants was estimated using MiXeR. Shared genetic architecture was assessed using a conjunctional false discovery rate framework, and mapped genes were included in gene-set enrichment analyses. Cortical structure and blood immune markers exhibited predominantly inverse phenotypic associations. There were modest genome-wide genetic correlations, the strongest of which were for C-reactive protein levels (r g_surface_area = −0.13, false discovery rate–corrected p = 4.17 × 10−3; r g_thickness = −0.13, false discovery rate–corrected p = 4.00 × 10−2). Meanwhile, local genetic correlations showed a mosaic of positive and negative associations. White blood cells shared on average 46.24% and 38.64% of trait-influencing genetic variants with surface area and thickness, respectively. Additionally, surface area shared 55 unique loci with the blood immune markers while thickness shared 15. Overall, monocyte count exhibited the largest genetic overlap with cortical brain structure. A series of gene enrichment analyses implicated neuronal-, astrocytic-, and schizophrenia-associated genes. The findings indicate shared genetic underpinnings for cortical brain structure and blood immune markers, with implications for neurodevelopment and understanding the etiology of brain-related disorders. [ABSTRACT FROM AUTHOR]

In the realm of cognitive science, the phenomenon of "successful cognitive aging" stands as a hallmark of individuals who exhibit cognitive abilities surpassing those of their age-matched counterparts. However, it is paramount to underscore a significant gap in the current research, which is marked by a paucity of comprehensive inquiries that deploy substantial sample sizes to methodically investigate the cerebral biomarkers and contributory elements underpinning this cognitive success. It is within this context that our present study emerges, harnessing data derived from the UK Biobank. In this study, a highly selective cohort of 1060 individuals aged 65 and above was meticulously curated from a larger pool of 17,072 subjects. The selection process was guided by their striking cognitive resilience, ascertained via rigorous evaluation encompassing both generic and specific cognitive assessments, compared to their peers within the same age stratum. Notably, the cognitive abilities of the chosen participants closely aligned with the cognitive acumen commonly observed in middle-aged individuals. Our study leveraged a comprehensive array of neuroimaging-derived metrics, obtained from three Tesla MRI scans (T1-weighted images, dMRI, and resting-state fMRI). The metrics included image-derived phenotypes (IDPs) that addressed grey matter morphology, the strength of brain network connectivity, and the microstructural attributes of white matter. Statistical analyses were performed employing ANOVA, Mann–Whitney U tests, and chi-square tests to evaluate the distinctive aspects of IDPs pertinent to the domain of successful cognitive aging. Furthermore, these analyses aimed to elucidate lifestyle practices that potentially underpin the maintenance of cognitive acumen throughout the aging process. Our findings unveiled a robust and compelling association between heightened cognitive aptitude and the integrity of white matter structures within the brain. Furthermore, individuals who exhibited successful cognitive aging demonstrated markedly enhanced activity in the cerebral regions responsible for auditory perception, voluntary motor control, memory retention, and emotional regulation. These advantageous cognitive attributes were mirrored in the health-related lifestyle choices of the surveyed cohort, characterized by elevated educational attainment, a lower incidence of smoking, and a penchant for moderate alcohol consumption. Moreover, they displayed superior grip strength and enhanced walking speeds. Collectively, these findings furnish valuable insights into the multifaceted determinants of successful cognitive aging, encompassing both neurobiological constituents and lifestyle practices. Such comprehensive comprehension significantly contributes to the broader discourse on aging, thereby establishing a solid foundation for the formulation of targeted interventions aimed at fostering cognitive well-being among aging populations. [ABSTRACT FROM AUTHOR]

Sleep and depression have a complex, bidirectional relationship, with sleep-associated alterations in brain dynamics and structure impacting a range of symptoms and cognitive abilities. Previous work describing these relationships has provided an incomplete picture by investigating only one or two types of sleep measures, depression, or neuroimaging modalities in parallel. We analyze the correlations between brainwide neural signatures of sleep, cognition, and depression in task and resting-state data from over 30,000 individuals from the UK Biobank and Human Connectome Project. Neural signatures of insomnia and depression are negatively correlated with those of sleep duration measured by accelerometer in the task condition but positively correlated in the resting-state condition. Our results show that resting-state neural signatures of insomnia and depression resemble that of rested wakefulness. This is further supported by our finding of hypoconnectivity in task but hyperconnectivity in resting-state data in association with insomnia and depression. These observations dispute conventional assumptions about the neurofunctional manifestations of hyper- and hypo-somnia, and may explain inconsistent findings in the literature. The associations between sleep, depression and brain activity are not well understood. Here, the authors show patterns of brain activity associated with insomnia and depression resemble those found in people who sleep less, but only under cognitive load. At rest, these activation patterns are hyperconnected and resemble those found in longer sleepers. [ABSTRACT FROM AUTHOR]

The relationship between obesity and human brain structure is incompletely under)stood. Using diffusion-weighted MRI from ∼30,000 UK Biobank participants, we test the hypothesis that obesity (waist-to-hip ratio, WHR) is associated with regional differences in two micro-structural MRI metrics: isotropic volume fraction (ISOVF), an index of free water, and intra-cellular volume fraction (ICVF), an index of neurite density. We observed significant associations with obesity in two coupled but distinct brain systems: a prefrontal/temporal/striatal system associated with ISOVF and a medial temporal/occipital/striatal system associated with ICVF. The ISOVF~WHR system colocated with expression of genes enriched for innate immune functions, decreased glial density, and high mu opioid (MOR) and other neurotransmitter receptor density. Conversely, the ICVF~WHR system co-located with expression of genes enriched for G-protein coupled receptors and decreased density of MOR and other receptors. To test whether these distinct brain phenotypes might differ in terms of their underlying shared genetics or relationship to maps of the inflammatory marker C-reactive Protein (CRP), we estimated the genetic correlations between WHR and ISOVF (rg = 0.026, P = 0.36) and ICVF (rg = 0.112, P < 9×10−4) as well as comparing correlations between WHR maps and equivalent CRP maps for ISOVF and ICVF (P<0.05). These correlational results are consistent with a two-way mechanistic model whereby genetically determined differences in neurite density in the medial temporal system may contribute to obesity, whereas water content in the prefrontal system could reflect a consequence of obesity mediated by innate immune system activation. [ABSTRACT FROM AUTHOR]

Happiness is a fundamental human affective trait, but its biological basis is not well understood. Using a novel approach, we construct LDpred-inf polygenic scores of a general happiness measure in 2 cohorts: the Adolescent Brain Cognitive Development (ABCD) cohort (N = 15,924, age range 9.23–11.8 years), the Add Health cohort (N = 9129, age range 24.5–34.7) to determine associations with several well-being and happiness measures. Additionally, we investigated associations between genetic scores for happiness and brain structure in ABCD (N = 9626, age range (8.9–11) and UK Biobank (N = 16,957, age range 45–83). We detected significant (p.FDR < 0.05) associations between higher genetic scores vs. several well-being measures (best r2 = 0.019) in children of multiple ancestries in ABCD and small yet significant correlations with a happiness measure in European participants in Add Health (r2 = 0.004). Additionally, we show significant associations between lower genetic scores for happiness with smaller structural brain phenotypes in a white British subsample of UK Biobank and a white sub-sample group of ABCD. We demonstrate that the genetic basis for general happiness level appears to have a consistent effect on happiness and wellbeing measures throughout the lifespan, across multiple ancestral backgrounds, and multiple brain structures. [ABSTRACT FROM AUTHOR]

Background: The early adversity is associated with a series of negative outcomes in adulthood, and the impact on the cerebral cortex may be one of the fundamental causes of these adverse consequences in adulthood. In this study, we aim to investigate the causal relationship between early adversity and changes in cerebral cortex structure using Mendelian randomization (MR) analysis. Methods: The GWAS summary statistics of 6 early adversity traits were obtained from individuals of European ancestry in the UK Biobank. The GWAS summary statistics of 34 known functional cortical regions were obtained from the ENIGMA Consortium. Causal relationships between the adversity factors and brain cortical structure were assessed using the inverse-variance weighted (IVW), MR-Egger, and weighted median methods, with IVW being the primary evaluation method. Cochran's Q-test, MR-PRESSO, leave-one-out analysis, and funnel plot examination were employed to detect potential heterogeneity and pleiotropy, as well as to identify and exclude outliers. Results: At a global level, no causal relationship was found between early adversity and cortical thickness (TH) or surface area (SA) of the brain. However, at the regional level, early adversity was found to potentially influence the TH of the caudal anterior cingulate, superior temporal, entorhinal, paracentral, lateral occipital, banks of the superior temporal sulcus, and supramarginal regions, as well as the SA of the pars triangularis, lateral occipital, parahippocampal, medial orbitofrontal, and isthmus cingulate regions. All findings were nominally significant and passed sensitivity analyses, with no significant heterogeneity or pleiotropy detected. Discussion: Our study provides evidence for the association between early adversity and alterations in brain cortical structure, which may serve as a foundation for certain mental disorders. Furthermore, magnetic resonance imaging (MRI) might be considered as a promising tool to aid healthcare professionals in identifying individuals with a history of adverse experiences, allowing for early interventions. [ABSTRACT FROM AUTHOR]

Modifiable lifestyle factors have been shown to promote healthy brain ageing. However, studies have typically focused on a single factor at a time. Given that lifestyle factors do not occur in isolation, multivariable analyses provide a more realistic model of the lifestyle-brain relationship. Here, canonical correlation analyses (CCA) examined the relationship between nine lifestyle factors and seven MRI-derived indices of brain structure. The resulting covariance pattern was further explored with Bayesian regressions. CCA analyses were first conducted on a Danish cohort of older adults (n = 251) and then replicated in a British cohort (n = 668). In both cohorts, the latent factors of lifestyle and brain structure were positively correlated (UK: r =.37, p < 0.001; Denmark: r =.27, p < 0.001). In the cross-validation study, the correlation between lifestyle-brain latent factors was r =.10, p = 0.008. However, the pattern of associations differed between datasets. These findings suggest that baseline characterisation and tailoring towards the study sample may be beneficial for achieving targeted lifestyle interventions. [ABSTRACT FROM AUTHOR]

Purpose: To examine the association between dietary magnesium (Mg) intake and brain volumes and white matter lesions (WMLs) in middle to early old age. Methods: Participants (aged 40–73 years) from UK Biobank (n = 6001) were included and stratified by sex. Dietary Mg was measured using an online computerised 24 h recall questionnaire to estimate daily Mg intake. Latent class analysis and hierarchical linear regression models were performed to investigate the association between baseline dietary Mg, Mg trajectories, and brain volumes and WMLs. Associations between baseline Mg, and baseline blood pressure (BP) measures, and baseline Mg, Mg trajectories and BP changes (between baseline and wave 2) were also investigated to assess whether BP mediates the link between Mg intake and brain health. All analyses controlled for health and socio-demographic covariates. Possible interactions between menopausal status and Mg trajectories in predicting brain volumes and WMLs were also investigated. Results: On average, higher baseline dietary Mg intake was associated with larger brain volumes (gray matter [GM]: 0.001% [SE = 0.0003]; left hippocampus [LHC]: 0.0013% [SE = 0.0006]; and right hippocampus [RHC]: 0.0023% [SE = 0.0006]) in both men and women. Latent class analysis of Mg intake revealed three classes: "high-decreasing" (men = 3.2%, women = 1.9%), "low-increasing" (men = 1.09%, women = 1.62%), and "stable normal" (men = 95.71%, women = 96.51%). In women, only the "high-decreasing" trajectory was significantly associated with larger brain volumes (GM: 1.17%, [SE = 0.58]; and RHC: 2.79% [SE = 1.11]) compared to the "normal-stable", the "low-increasing" trajectory was associated with smaller brain volumes (GM: − 1.67%, [SE = 0.30]; white matter [WM]: − 0.85% [SE = 0.42]; LHC: − 2.43% [SE = 0.59]; and RHC: − 1.50% [SE = 0.57]) and larger WMLs (1.6% [SE = 0.53]). Associations between Mg and BP measures were mostly non-significant. Furthermore, the observed neuroprotective effect of higher dietary Mg intake in the "high-decreasing" trajectory appears to be greater in post-menopausal than pre-menopausal women. Conclusions: Higher dietary Mg intake is related to better brain health in the general population, and particularly in women. [ABSTRACT FROM AUTHOR]

The cognitive reserve (CR) hypothesis is reinforced by negative moderating effects, suggesting that those with higher CR are less reliant on brain structure for cognitive function. Previous research on CR's moderating effects yielded inconsistent results, motivating our 3 studies using UK Biobank data. Study I examined five CR proxies' moderating effects on global, lobar, and regional brain-cognition models; study II extended study I by using a larger sample size; and study III investigated age-related moderating effects on the hippocampal regions. In study I, most moderating effects were negative and none survived the multiple comparison correction, but study II identified 13 global-level models with significant negative moderating effects that survived correction. Study III showed age influenced CR proxies' moderating effects in hippocampal regions. Our findings suggest that the effects of CR proxies on brain integrity and cognition varied depending on the proxy used, brain integrity indicators, cognitive domain, and age group. This study offers significant insights regarding the importance of CR for brain integrity and cognitive outcomes. [ABSTRACT FROM AUTHOR]

In this study, we aimed to investigate the causal associations of brain structure with bone mineral density (BMD). Based on the genome-wide association study (GWAS) summary statistics of 1 325 brain imaging-derived phenotypes (BIDPs) of brain structure from the UK Biobank and GWAS summary datasets of 5 BMD locations, including the total body, femoral neck, lumbar spine, forearm, and heel from the GEFOS Consortium, linkage disequilibrium score regression (LDSC) was conducted to determine the genetic correlations, and Mendelian randomization (MR) was then performed to explore the causal relationship between the BIDPs and BMD. Several sensitivity analyses were performed to verify the strength and stability of the present MR outcomes. To increase confidence in our findings, we also performed confirmatory MR between BIDPs and osteoporosis. LDSC revealed that 1.93% of BIDPs, with a false discovery rate (FDR) < 0.01, were genetically correlated with BMD. Additionally, we observed that 1.31% of BIDPs exhibited a significant causal relationship with BMD (FDR < 0.01) through MR. Both the LDSC and MR results demonstrated that the BIDPs "Volume of normalized brain," "Volume of gray matter in Left Inferior Frontal Gyrus, pars opercularis," "Volume of Estimated Total Intra Cranial" and "Volume-ratio of brain segmentation/estimated total intracranial" had strong associations with BMD. Interestingly, our results showed that more left BIDPs were causally associated with BMD, especially within and around the left frontal region. In conclusion, a part of the brain structure causally influences BMD, which may provide important perspectives for the prevention of osteoporosis and offer valuable insights for further research on the brain-bone axis. [ABSTRACT FROM AUTHOR]

Many sleep less than recommended without experiencing daytime sleepiness. According to prevailing views, short sleep increases risk of lower brain health and cognitive function. Chronic mild sleep deprivation could cause undetected sleep debt, negatively affecting cognitive function and brain health. However, it is possible that some have less sleep need and are more resistant to negative effects of sleep loss. We investigated this using a cross-sectional and longitudinal sample of 47,029 participants of both sexes (20-89 years) from the Lifebrain consortium, Human Connectome project (HCP) and UK Biobank (UKB), with measures of self-reported sleep, including 51,295 MRIs of the brain and cognitive tests. A total of 740 participants who reported to sleep, 6 h did not experience daytime sleepiness or sleep problems/disturbances interfering with falling or staying asleep. These short sleepers showed significantly larger regional brain volumes than both short sleepers with daytime sleepiness and sleep problems (n = 1742) and participants sleeping the recommended 7-8 h (n = 3886). However, both groups of short sleepers showed slightly lower general cognitive function (GCA), 0.16 and 0.19 SDs, respectively. Analyses using accelerometer-estimated sleep duration confirmed the findings, and the associations remained after controlling for body mass index, depression symptoms, income, and education. The results suggest that some people can cope with less sleep without obvious negative associations with brain morphometry and that sleepiness and sleep problems may be more related to brain structural differences than duration. However, the slightly lower performance on tests of general cognitive abilities warrants closer examination in natural settings. [ABSTRACT FROM AUTHOR]

Background: The correlations between genetic risk for Alzheimer's disease (AD) with comprehensive brain regions at a regional scale are still not well understood. We aim to explore whether these associations vary across different age stages. Methods: This study used large existing genome-wide association datasets to calculate polygenic risk score (PRS) for AD in two populations from the UK Biobank (N ~ 23 000) and Adolescent Brain Cognitive Development Study (N ~ 4660) who had multimodal macrostructural and microstructural magnetic resonance imaging (MRI) metrics. We used linear mixed-effect models to assess the strength of the association between AD PRS and multiple MRI metrics of regional brain structures at different stages of life. Results: Compared to those with lower PRSs, adolescents with higher PRSs had thinner cortex in the caudal anterior cingulate and supramarginal. In the middle-aged and elderly population, AD PRS had correlations with regional structure shrink primarily located in the cingulate, prefrontal cortex, hippocampus, thalamus, amygdala, and striatum, whereas the brain expansion was concentrated near the occipital lobe. Furthermore, both adults and adolescents with higher PRSs exhibited widespread white matter microstructural changes, indicated by decreased fractional anisotropy (FA) or increased mean diffusivity (MD). Conclusions: In conclusion, our results suggest genetic loading for AD may influence brain structures in a highly dynamic manner, with dramatically different patterns at different ages. This age-specific change is consistent with the classical pattern of brain impairment observed in AD patients. [ABSTRACT FROM AUTHOR]

Background and aims Observational studies have linked elevated blood pressure (BP) to impaired cognitive function. However, the functional and structural changes in the brain that mediate the relationship between BP elevation and cognitive impairment remain unknown. Using observational and genetic data from large consortia, this study aimed to identify brain structures potentially associated with BP values and cognitive function. Methods and results Data on BP were integrated with 3935 brain magnetic resonance imaging-derived phenotypes (IDPs) and cognitive function defined by fluid intelligence score. Observational analyses were performed in the UK Biobank and a prospective validation cohort. Mendelian randomisation (MR) analyses used genetic data derived from the UK Biobank, International Consortium for Blood Pressure, and COGENT consortium. Mendelian randomisation analysis identified a potentially adverse causal effect of higher systolic BP on cognitive function [−0.044 standard deviation (SD); 95% confidence interval (CI) −0.066, −0.021] with the MR estimate strengthening (−0.087 SD; 95% CI −0.132, −0.042), when further adjusted for diastolic BP. Mendelian randomisation analysis found 242, 168, and 68 IDPs showing significant (false discovery rate P < 0.05) association with systolic BP, diastolic BP, and pulse pressure, respectively. Most of these IDPs were inversely associated with cognitive function in observational analysis in the UK Biobank and showed concordant effects in the validation cohort. Mendelian randomisation analysis identified relationships between cognitive function and the nine of the systolic BP-associated IDPs, including the anterior thalamic radiation, anterior corona radiata, or external capsule. Conclusion Complementary MR and observational analyses identify brain structures associated with BP, which may be responsible for the adverse effects of hypertension on cognitive performance. [ABSTRACT FROM AUTHOR]

Previous research has linked specific modifiable lifestyle factors to age-related cognitive decline in adults. Little is known about the potential role of an overall healthy lifestyle in brain structure. We examined the association of adherence to a healthy lifestyle with a panel of brain structural markers among 2,413 participants in PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study in China and 19,822 participants in UK Biobank (UKB). A healthy lifestyle score (0–5) was constructed based on five modifiable lifestyle factors: diet, physical activity, smoking, alcohol consumption, and body mass index. Validated multimodal neuroimaging markers were derived from brain magnetic resonance imaging. In the cross-sectional analysis of PRECISE, participants who adopted four or five low-risk lifestyle factors had larger total brain volume (TBV; β = 0.12, 95% CI: − 0.02, 0.26; p-trend = 0.05) and gray matter volume (GMV; β = 0.16, 95% CI: 0.01, 0.30; p-trend = 0.05), smaller white matter hyperintensity volume (WMHV; β = − 0.35, 95% CI: − 0.50, − 0.20; p-trend < 0.001) and lower odds of lacune (Odds Ratio [OR] = 0.48, 95% CI: 0.22, 1.08; p-trend = 0.03), compared to those with zero or one low-risk factors. Meanwhile, in the prospective analysis in UKB (with a median of 7.7 years' follow-up), similar associations were observed between the number of low-risk lifestyle factors (4–5 vs. 0–1) and TBV (β = 0.22, 95% CI: 0.16, 0.28; p-trend < 0.001), GMV (β = 0.26, 95% CI: 0.21, 0.32; p-trend < 0.001), white matter volume (WMV; β = 0.08, 95% CI: 0.01, 0.15; p-trend = 0.001), hippocampus volume (β = 0.15, 95% CI: 0.08, 0.22; p-trend < 0.001), and WMHV burden (β = − 0.23, 95% CI: − 0.29, − 0.17; p-trend < 0.001). Those with four or five low-risk lifestyle factors showed approximately 2.0–5.8 years of delay in aging of brain structure. Adherence to a healthier lifestyle was associated with a lower degree of neurodegeneration-related brain structural markers in middle-aged and older adults. [ABSTRACT FROM AUTHOR]

Some lifestyle factors are related to health and brain function and structure, but the brain systems involved are incompletely understood. A general linear model was used to test the associations of the combined and separate lifestyle risk measures of alcohol use, smoking, diet, amounts of physical activity, leisure activity, and mobile phone use, with brain functional connectivity with the high resolution Human Connectome Project (HCP) atlas in 19,415 participants aged 45–78 from the UK Biobank, with replication with HCP data. Higher combined lifestyle risk scores were associated with lower functional connectivity across the whole brain, but especially of three brain systems. Low physical, and leisure and social, activity were associated with low connectivities of the somatosensory/motor cortical regions and of hippocampal memory‐related regions. Low mobile phone use, perhaps indicative of poor social communication channels, was associated with low functional connectivity of brain regions in and related to the superior temporal sulcus that are involved in social behavior and face processing. Smoking was associated with lower functional connectivity of especially frontal regions involved in attention. Lower cortical thickness in some of these regions, and also lower subcortical volume of the hippocampus, amygdala, and globus pallidus, were also associated with the sum of the poor lifestyle scores. This very large scale analysis emphasizes how the lifestyle of humans relates to their brain structure and function, and provides a foundation for understanding the causalities that relate to the differences found here in the brains of different individuals. [ABSTRACT FROM AUTHOR]

Introduction: TV viewing in the elderly and in children is associated with subsequent greater decline of various cognitive functions including verbal working memory, but results of its association with subsequent risk of dementia were divided. Methods: In this longitudinal cohort study of UK Biobank, we investigated the associations of TV viewing length with subsequent risk of dementia and longitudinal changes of brain structural measures after corrections of a wide range of potential confounders. Results: Our results showed longer TV viewing was associated with increased risk of subsequent onset of dementia, as well as subsequent greater decline in intracellular volume fraction (ICVF) in the extensive areas of right lateral temporal cortex and the rightmedial temporal cortex, in the area around the leftmiddle and inferior temporal cortex as well as the left fusiform gyrus, and the area adjacent to the left inferior frontal gyrus, and left insula. Discussion: These results may suggest prolonged TV viewing was associated with decline in density of neurites (axon, dendrites) in areas particularly implicated in language, communication, and memory, which are altered in dementia. [ABSTRACT FROM AUTHOR]

Disrupted brain structures and several life environmental factors have been shown to influence depression and anxiety, but their interactions with anxiety and depression remain elusive. Genome‐wide association study datasets of 15 brain structure longitudinal changes (N = 15,640) were obtained from the published study. Genotype and phenotype‐related data of depression, anxiety, and life environmental factors (including smoking, alcohol drinking, coffee intake, maternal smoking, physical activity, vitamin D, insomnia, sleep duration, and family satisfaction) were collected from UK Biobank. We calculated the polygenic risk scores (PRS) of 15 brain structure changes and then conducted linear regression analyses to explore the interactions of brain structure changes and life environmental factors on depression and anxiety using 15 brain structure change‐related PRS, life environmental factors and interactions of them as instrumental variables, and depression score or anxiety score as outcomes. Sex stratification in all analyses was performed to reveal sex‐specific differences in the interactions. We found 14 shared interactions related to both depression and anxiety in total sample, such as alcohol drinking × cerebellum white matter 3 (WM; beta = −.003, p =.018 for depression; beta = −003, p =.008 for anxiety) and maternal smoking × nucleus accumbens 2 (beta =.088, p =.002 for depression; beta =.070, p =.008 for anxiety). We also observed sex‐specific differences in the interactions, for instance, alcohol drinking × cerebellum WM 3 was negatively associated with depression and anxiety in males (beta = −.004, p =.020 for depression; beta = −.005, p =.002 for anxiety). Our study results reveal the important interactions between brain structure changes and several life environmental factors on depression and anxiety, which may help to explore the pathogenesis of depression and anxiety. [ABSTRACT FROM AUTHOR]

Aims: To investigate the association of type 1 diabetes (T1D) and age at diagnosis of type 2 diabetes (T2D) with brain structure and incident dementia. Methods: Our analysis was based on the UK Biobank. We included 1376 participants with diabetes and 2752 randomly selected controls for brain volume analysis, and 25,141 participants with diabetes and 50,282 randomly selected controls for dementia analysis. Brain volume was measured using magnetic resonance imaging. Dementia was identified using hospital inpatient records and mortality register data until January 2021. Results: T2D diagnosed at a younger age was associated with larger reductions in brain volume. After adjustment for glycated haemoglobin (HbA1c) and other covariates, only T2D diagnosed <50 years was associated with smaller total brain volume (β (95% CI): −14.56 (−24.67, −4.44) ml), and grey (−6.47[−12.75, −0.20] ml) and white matter volumes (−8.08[−14.66, −1.51] ml). Corresponding numbers for total brain, grey matter and white matter volumes associated with T1D were −62.86 (−93.71,‐32.01), −34.27 (−53.72, −14.83), and −28.59 (−47.65, −9.52) ml, respectively. During a median follow‐up of 11.9 years, 2035 new dementia cases were identified. Younger age at diagnosis of T2D was associated with larger excessive risk of dementia, whereas T2D diagnosed <50 years was associated with the largest hazard ratio (HR) (95% CI: 2.03[1.53–2.69]) in the multivariable analysis. The HR (95% CI) for dementia associated with T1D was 2.08 (1.40–3.09). Conclusion: Individuals with T1D or T2D diagnosed at younger age are at larger excessive risk of brain volume reduction and dementia. [ABSTRACT FROM AUTHOR]

Introduction. Childhood trauma and adversity are common across societies and have strong associations with physical and psychiatric morbidity throughout the life-course. One possible mechanism through which childhood trauma may predispose individuals to poor psychiatric outcomes is via associations with brain structure. This study aimed to elucidate the associations between childhood trauma and brain structure across two large, independent community cohorts. Methods. The two samples comprised (i) a subsample of Generation Scotland (n=1,024); and (ii) individuals from UK Biobank (n=27,202). This comprised n=28,226 for mega-analysis. MRI scans were processed using Free Surfer, providing cortical, subcortical, and global brain metrics. Regression models were used to determine associations between childhood trauma measures and brain metrics and psychiatric phenotypes. Results. Childhood trauma associated with lifetime depression across cohorts (OR 1.06 GS, 1.23 UKB), and related to early onset and recurrent course within both samples. There was evidence for associations between childhood trauma and structural brain metrics. This included reduced global brain volume, and reduced cortical surface area with highest effects in the frontal (β=-0.0385, SE=0.0048, p(FDR)=5.43x10-15) and parietal lobes (β=-0.0387, SE=0.005, p(FDR)=1.56x10-14). At a regional level the ventral diencephalon (VDc) displayed significant associations with childhood trauma measures across both cohorts and at mega-analysis (β=-0.0232, SE=0.0039, p(FDR)=2.91x10-8). There were also associations with reduced hippocampus, thalamus, and nucleus accumbens volumes. Discussion. Associations between childhood trauma and reduced global and regional brain volumes were found, across two independent UK cohorts, and at mega-analysis. This provides robust evidence for a lasting effect of childhood adversity on brain structure. [ABSTRACT FROM AUTHOR]

Wellbeing, an important component of mental health, is influenced by genetic and environmental factors. Previous association studies between brain structure and wellbeing have typically focused on volumetric measures and employed small cohorts. Using the UK Biobank Resource, we explored the relationships between wellbeing and brain morphometrics (volume, thickness and surface area) at both phenotypic and genetic levels. The sample comprised 38,982 participants with neuroimaging and wellbeing phenotype data, of which 19,234 had genotypes from which wellbeing polygenic scores (PGS) were calculated. We examined the association of wellbeing phenotype and PGS with all brain regions (including cortical, subcortical, brainstem and cerebellar regions) using multiple linear models, including (1) basic neuroimaging covariates and (2) additional demographic factors that may synergistically impact wellbeing and its neural correlates. Genetic correlations between genomic variants influencing wellbeing and brain structure were also investigated. Small but significant associations between wellbeing and volumes of several cerebellar structures (β = 0.015–0.029, PFDR = 0.007–3.8 × 10−9), brainstem, nucleus accumbens and caudate were found. Cortical associations with wellbeing included volume of right lateral occipital, thickness of bilateral lateral occipital and cuneus, and surface area of left superior parietal, supramarginal and pre‐/post‐central regions. Wellbeing‐PGS was associated with cerebellar volumes and supramarginal surface area. Small mediation effects of wellbeing phenotype and PGS on right VIIIb cerebellum were evident. No genetic correlation was found between wellbeing and brain morphometric measures. We provide a comprehensive overview of wellbeing‐related brain morphometric variation. Notably, small effect sizes reflect the multifaceted nature of this concept. [ABSTRACT FROM AUTHOR]

Abstract Background: Altered expression of the complement component C4A gene is a known risk factor for schizophrenia. Further, predicted brain C4A expression has also been associated with memory function highlighting that altered C4A expression in the brain may be relevant for cognitive and behavioral traits. Methods: We obtained genetic information and performance measures on seven cognitive tasks for up to 329 773 individuals from the UK Biobank, as well as brain imaging data for a subset of 33 003 participants. Direct genotypes for variants (n = 3213) within the major histocompatibility complex region were used to impute C4 structural variation, from which predicted expression of the C4A and C4B genes in human brain tissue were predicted. We investigated if predicted brain C4A or C4B expression were associated with cognitive performance and brain imaging measures using linear regression analyses. Results: We identified significant negative associations between predicted C4A expression and performance on select cognitive tests, and significant associations with MRI-based cortical thickness and surface area in select regions. Finally, we observed significant inconsistent partial mediation of the effects of predicted C4A expression on cognitive performance, by specific brain structure measures. Conclusions: These results demonstrate that the C4 risk locus is associated with the central endophenotypes of cognitive performance and brain morphology, even when considered independently of other genetic risk factors and in individuals without mental or neurological disorders. [ABSTRACT FROM AUTHOR]

Background: Resting heart rate (RHR) has been linked with an increased risk of dementia. However, evidence characterizing the associations of RHR with different dementia subtypes and their underlying mechanisms remains scarce. This study aims to investigate the relationships of RHR with different dementia types, cognitive function, and brain structural abnormalities. Methods: Three hundred thirty-nine thousand nine hundred one participants with no prior diagnosis of dementia from the UK biobank were analyzed. Cox regression and restricted cubic spline models examined the associations between RHR with all-cause dementia (ACD) and its major subtypes—Alzheimer's disease (AD) and vascular dementia (VaD). Logistic regression models assessed the associations of RHR with cognitive function, and linear regression models estimated the associations with hippocampal subfield volume and white matter tract integrity indexed by magnetic resonance imaging data. Results: During an average of 3148 (± 941.08) days of follow-up, 4177 individuals were diagnosed with dementia, including 2354 AD and 989 VaD cases. RHR ≥ 80bpm was associated with ACD (HR: 1.18, 95% CI: 1.08–1.28, P < 0.001) and VaD (HR: 1.29, 95% CI: 1.08–1.54, P = 0.005) but not AD in multi-adjusted models. A 10-bpm increment of RHR demonstrated non-linear effects in VaD, consisting of J-shape relationships. Several heterogeneities were indicated in stratified analysis, in which RHR measures only showed associations with dementia incidents in relatively younger populations (age ≤ 65) and females. Apart from dementia analysis, elevated RHR was associated with worsening performance in fluid intelligence and reaction time of cognitive tasks, decreased hippocampal subfields volume, and poor white matter tract integrity. Conclusions: RHR is associated with increased risks of ACD and VaD but also presented with few heterogeneities across different sex and age groups. Elevated RHR also appears to have deleterious effects on cognitive function and is distinctively associated with volume reduction in hippocampal subfields and impaired white matter tract integrity. [ABSTRACT FROM AUTHOR]

Alterations in brain size and organization represent some of the most distinctive changes in the emergence of our species. Yet, there is limited understanding of how genetic factors contributed to altered neuroanatomy during human evolution. Here, we analyze neuroimaging and genetic data from up to 30,000 people in the UK Biobank and integrate with genomic annotations for different aspects of human evolution, including those based on ancient DNA and comparative genomics. We show that previously reported signals of recent polygenic selection for cortical anatomy are not replicable in a more ancestrally homogeneous sample. We then investigate relationships between evolutionary annotations and common genetic variants shaping cortical surface area and white-matter connectivity for each hemisphere. Our analyses identify single-nucleotide polymorphism heritability enrichment in human-gained regulatory elements that are active in early brain development, affecting surface areas of several parts of the cortex, including left-hemispheric speech-associated regions. We also detect heritability depletion in genomic regions with Neanderthal ancestry for connectivity of the uncinate fasciculus; this is a white-matter tract involved in memory, language, and socioemotional processing with relevance to neuropsychiatric disorders. Finally, we show that common genetic loci associated with left-hemispheric pars triangularis surface area overlap with a human-gained enhancer and affect regulation of ZIC4, a gene implicated in neurogenesis. This work demonstrates how genomic investigations of present-day neuroanatomical variation can help shed light on the complexities of our evolutionary past. [ABSTRACT FROM AUTHOR]

Background: Grip strength is a widely used and well-validated measure of overall health that is increasingly understood to index risk for psychiatric illness and neurodegeneration in older adults. However, existing work has not examined how grip strength relates to a comprehensive set of mental health outcomes, which can detect early signs of cognitive decline. Furthermore, whether brain structure mediates associations between grip strength and cognition remains unknown.Methods: Based on cross-sectional and longitudinal data from over 40,000 participants in the UK Biobank, this study investigated the behavioral and neural correlates of handgrip strength using a linear mixed effect model and mediation analysis.Results: In cross-sectional analysis, we found that greater grip strength was associated with better cognitive functioning, higher life satisfaction, greater subjective well-being, and reduced depression and anxiety symptoms while controlling for numerous demographic, anthropometric, and socioeconomic confounders. Further, grip strength of females showed stronger associations with most behavioral outcomes than males. In longitudinal analysis, baseline grip strength was related to cognitive performance at ~9 years follow-up, while the reverse effect was much weaker. Further, baseline neuroticism, health, and financial satisfaction were longitudinally associated with subsequent grip strength. The results revealed widespread associations between stronger grip strength and increased grey matter volume, especially in subcortical regions and temporal cortices. Moreover, grey matter volume of these regions also correlated with better mental health and considerably mediated their relationship with grip strength.Conclusions: Overall, using the largest population-scale neuroimaging dataset currently available, our findings provide the most well-powered characterization of interplay between grip strength, mental health, and brain structure, which may facilitate the discovery of possible interventions to mitigate cognitive decline during aging. [ABSTRACT FROM AUTHOR]

Anatomy Nights is an international public engagement event created to bring anatomy and anatomists back to public spaces with the goal of increasing the public's understanding of their own anatomy by comparison with non-human tissues. The event consists of a 30-minute mini-lecture on the anatomy of a specific anatomical organ followed by a dissection of animal tissues to demonstrate the same organ anatomy. Before and after the lecture and dissection, participants complete research surveys designed to assess prior knowledge and knowledge gained as a result of participation in the event, respectively. This study reports the results of Anatomy Nights brain events held at four different venues in the UK and USA in 2018 and 2019. Two general questions were asked of the data: 1) Do participant post-event test scores differ from pre-event scores; and 2) Are there differences in participant scores based on location, educational background, and career. We addressed these questions using a combination of generalized linear models (R's glm function; R version 4.1.0 [R Core Team, 2014]) that assumed a binomial distribution and implemented a logit link function, as well as likelihood estimates to compare models. Survey data from 91 participants indicate that scores improve on post-event tests compared to pre-event tests, and these results hold irrespective of location, educational background, and career. In the pre-event tests, participants performed well on naming structures with an English name (frontal lobe and brainstem), and showed signs of improvement on other anatomical names in the post-test. Despite this improvement in knowledge, we found no evidence that participation in Anatomy Nights improved participants' ability to apply this knowledge to neuroanatomical contexts (e.g., stroke). [ABSTRACT FROM AUTHOR]

The relationship between obesity and neurocognitive consequences is complex. Here we investigated associations between body mass index (BMI) and subsequent changes in brain structures, cognitive changes, and the onset of dementia after adjustment of a wide range of potential confounding variables using a large prospective cohort data of UK Biobank. After correcting for confounding factors, higher BMI was associated with greater retention in visuospatial memory performance (decline in error numbers) [beta = -0.019 (CI:-0.027~-0.016), N = 39191], increase in depression tendency scores [beta = 0.036(0.027~0.045)] as well as decreased risk of incident dementia [increasing BMI by 1 is associated with HR of 0.981 (CI:0.969~0.992), N = 398782], but not changes in fluid intelligence or reaction time. Whole brain multiple regression analyses (volumetric analyses: N = 1253, other analyses: N = 1241) revealed positive associations between BMI and subsequent changes in regional gray matter volume (rGMV) in multiple areas, regional white matter volume changes in widespread white matter (WM) tracts, fractional anisotropy changes in several tracts, and intracellular volume fraction (ICVF) and orientation dispersion (OD) in widespread areas, and isotropic volume fraction (ISOVF) in a few areas, and negative associations between BMI and subsequent changes in rGMV in the bilateral medial temporal lobe areas, mean, axial and radial diffusivity, and ISOVF in widespread areas. These results are mostly consistent with the view that less BMI precedes greater neurocognitive aging or atrophy, with a few exceptions including OD findings and the rGMV finding of the medial temporal lobes as most of significant longitudinal associations of higher BMI were opposite to those seen in higher age and dementia. Future epidemiological studies should consider separating effects of higher BMI itself from potential confounders. [ABSTRACT FROM AUTHOR]

Few studies have investigated brain responses to different art media. Investigations into brain processes during art making have highlighted important structures. Neuroimaging tools have been used to investigate activation of brain areas whilst artmaking, but not in a therapeutic setting. This review highlights recent advancements in this area and encourages researchers to be the first to apply this in the UK. To understand how the principles of neuroscience are currently informing the literature to explain the effects of art media in art therapy practice. Review of published peer-reviewed research between years 2000 and 2020 on neuroscience and art therapy. Findings were summarised into categories discussing psychological/neurobiological issues, art media, neuroimaging technology, and models posited. Forty-six studies were found; majority discussed the structure and function of the brain to explain art therapy processes. The Expressive Therapies Continuum (ETC) model theorised that media properties stimulate different levels of visual and cognitive processing. The novel Mobile Brain/Body Imaging (MoBI) neuroimaging technology may be used as a means of quantifying data. Significant progress has been made in attempting to explain brain responses during the art therapy process. However empirical data is needed to prove theoretical models. The use of neuroimaging has started this process to lead research into evidence-based practice. Evidencing the ground-breaking ETC model, using neuroimaging and MoBI technology is needed through close collaboration between transdisciplinary departments. Art therapists should be encouraged to use the ETC to inform art therapy assessment, planning and treatment. Neuroscience is the study of the brain and its processes, and recently technology has been available to researchers to examine brain processes in detail. This systematic narrative review explores recent literature that uses the principles of neuroscience to investigate the effects of art therapy, with a specific interest in art media. A systematic narrative review is when the findings of the study rely on the use of words to summarise the data. Art media is an important part of art therapy, as it is through artistic expressions that the client communicates their inner troubles. Different art media has been shown to elicit different feelings and behavioural responses in clients. However, research showing brain responses to different art media is limited. This study highlights ways in which further research in this field can take place. Results show that significant advancements have already been made that identify important structures and functions of the brain accessed during art therapy. Important models which incorporate neuroscience principles and theorise the art therapy process are highlighted. A significant model is the Expressive Therapies Continuum. This model explains how the brain processes information when different art media is used. However empirical data is needed to substantiate the theory behind this model. The use of neuroimaging technology is one way to achieve this. Therefore, this paper encourages transdisciplinary research to further investigate the effects different art media has on the brain during the art therapy process. [ABSTRACT FROM AUTHOR]

Aim: To understand the impact of diabetes and co‐morbid hypertension on cognitive and brain health. Materials and Methods: We used data from the UK Biobank cohort consisting of ~500 000 individuals aged 40 to 69 years. Our outcomes included brain structural magnetic resonance imaging variables and cognitive function tests in a maximum of 38 918 individuals. We firstly tested associations with all outcomes between those with diabetes (n = 2043) and without (n = 36 875) and, secondly, compared those with co‐morbid diabetes/hypertension (n = 1283) with those with only diabetes (n = 760), hypertension (n = 9649) and neither disease (n = 27 226). Our analytical approach comprised linear regression models, with adjustment for a range of demographic and health factors. Standardized betas are reported. Results: Those with diabetes had worse brain and cognitive health for the majority of neuroimaging and cognitive measures, with the exception of g fractional anisotropy (white matter integrity), amygdala, pairs matching and tower rearranging. Compared with individuals with co‐morbid diabetes and hypertension, those with only hypertension had better brain health overall, with the largest difference observed in the pallidum (β =.189, 95% CI = 0.241; 0.137), while those with only diabetes differed in total grey volume (β =.150, 95% CI = 0.122; 0.179). Individuals with only diabetes had better verbal and numeric reasoning (β =.129, 95% CI = 0.077; 0.261), whereas those with only hypertension performed better on the symbol‐digit substitution task (β =.117, 95% CI = 0.048; 0.186). Conclusions: Individuals with co‐morbid diabetes and hypertension have worse brain and cognitive health compared with those with only one of these diseases. These findings potentially suggest that prevention of both diabetes and hypertension may delay changes in brain structure, as well as cognitive decline and dementia diagnosis. [ABSTRACT FROM AUTHOR]

Sleep is essential for life, including daily cognitive processes, yet the amount of sleep required for optimal brain health as we grow older is unclear. Poor memory and increased risk of dementia is associated with the extremes of sleep quantity and disruption of other sleep characteristics. We examined sleep and cognitive data from the UK Biobank (N = 479,420) in middle-to-late life healthy individuals (age 38–73 years) and the relationship with brain structure in a sub-group (N = 37,553). Seven hours of sleep per day was associated with the highest cognitive performance which decreased for every hour below and above this sleep duration. This quadratic relationship remained present in older individuals (>60 years, N = 212,006). Individuals who sleep between six-to-eight hours had significantly greater grey matter volume in 46 of 139 different brain regions including the orbitofrontal cortex, hippocampi, precentral gyrus, right frontal pole and cerebellar subfields. Several brain regions showed a quadratic relationship between sleep duration and volume while other regions were smaller only in individuals who slept longer. These findings highlight the important relationship between the modifiable lifestyle factor of sleep duration and cognition as well as a widespread association between sleep and structural brain health. Tai et al. examine sleep, cognitive and brain imaging data from middle-to-late life healthy individuals from the UK Biobank. They show that between six and eight hours of sleep duration is associated with the highest cognitive performance and larger grey matter volume in several areas of the brain. [ABSTRACT FROM AUTHOR]

Everybody likes to make a good prediction, in particular, when some sort of personal investment is involved in terms of finance, energy or time. The difficulty is to make a prediction that optimises the reward obtained from the original contribution; this is even more important when investments are the core service offered by a business or pension fund. The complexity of finance is that the human predictor may have other interests or bias than the human investor, the trust between predictor and investor will never be completely established as the investor will never know if the predictor has generated, intentionally or unintentionally, the optimum possible reward. This article presents the random neural network (RNN) in a recurrent configuration for the 4th industrial revolution on a Fintech application; the RNN is proposed to make predictions on time series data, specifically, prices. The biological model inspired by the brain structure and neural interconnections make predictions entirely on previous data from the time series rather than predictions based on several uncorrelated inputs. The model is validated against the property, stock and Fintech market: (1) UK property prices, (2) stock market indice prices, (3) cryptocurrency prices. Experimental results show that the proposed method makes accurate predictions on different investment portfolios. The prediction accuracy of the proposed RNN model is compared against long short-term memory (LSTM) and linear regression (LR) models. [ABSTRACT FROM AUTHOR]

Sex is a biological variable that contributes to individual variability in brain structure and behavior. Neuroimaging studies of population‐based samples have identified normative differences in brain structure between males and females, many of which are exacerbated in psychiatric and neurological conditions. Still, sex differences in MRI outcomes are understudied, particularly in clinical samples with known sex differences in disease risk, prevalence, and expression of clinical symptoms. Here we review the existing literature on sex differences in adult brain structure in normative samples and in 14 distinct psychiatric and neurological disorders. We discuss commonalities and sources of variance in study designs, analysis procedures, disease subtype effects, and the impact of these factors on MRI interpretation. Lastly, we identify key problems in the neuroimaging literature on sex differences and offer potential recommendations to address current barriers and optimize rigor and reproducibility. In particular, we emphasize the importance of large‐scale neuroimaging initiatives such as the Enhancing NeuroImaging Genetics through Meta‐Analyses consortium, the UK Biobank, Human Connectome Project, and others to provide unprecedented power to evaluate sex‐specific phenotypes in major brain diseases. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to evaluate whether engagement in leisure activities is linked to measures of brain structure, functional connectivity, and cognition in early old age. Methods: We examined data collected from 7,152 participants of the United Kingdom Biobank (UK Biobank) study. Weekly participation in six leisure activities was assessed twice and a cognitive battery and 3T MRI brain scan were administered at the second visit. Based on responses collected at two time points, individuals were split into one of four trajectory groups: (1) stable low engagement, (2) stable weekly engagement, (3) low to weekly engagement, and (4) weekly to low engagement. Results: Consistent weekly attendance at a sports club or gym was associated with connectivity of the sensorimotor functional network with the lateral visual (β = 0.12, 95%CI = [0.07, 0.18], FDR q = 2.48 × 10–3) and cerebellar (β = 0.12, 95%CI = [0.07, 0.18], FDR q = 1.23 × 10–4) networks. Visiting friends and family across the two timepoints was also associated with larger volumes of the occipital lobe (β = 0.15, 95%CI = [0.08, 0.21], FDR q = 0.03). Additionally, stable and weekly computer use was associated with global cognition (β = 0.62, 95%CI = [0.35, 0.89], FDR q = 1.16 × 10–4). No other associations were significant (FDR q > 0.05). Discussion: This study demonstrates that not all leisure activities contribute to cognitive health equally, nor is there one unifying neural signature across diverse leisure activities. [ABSTRACT FROM AUTHOR]

Brain age is a widely used index for quantifying individuals' brain health as deviation from a normative brain aging trajectory. Higher- than- expected brain age is thought partially to reflect above- average rate of brain aging. Here, we explicitly tested this assumption in two independent large test datasets (UK Biobank [main] and Lifebrain [replication]; longitudinal observations ≈ 2750 and 4200) by assessing the relationship between cross- sectional and longitudinal estimates of brain age. Brain age models were estimated in two different training datasets (n ≈ 38,000 [main] and 1800 individuals [replication]) based on brain structural features. The results showed no association between cross- sectional brain age and the rate of brain change measured longitudinally. Rather, brain age in adulthood was associated with the congenital factors of birth weight and polygenic scores of brain age, assumed to reflect a constant, lifelong influence on brain structure from early life. The results call for nuanced interpretations of cross- sectional indices of the aging brain and question their validity as markers of ongoing within- person changes of the aging brain. Longitudinal imaging data should be preferred whenever the goal is to understand individual change trajectories of brain and cognition in aging. [ABSTRACT FROM AUTHOR]

Background: Higher quality diets may be related to lower dementia rates. Midlife is emerging as a critical life stage for a number of dementia risk factors.Objective: This study examines whether diet quality is related to brain structure during midlife, and if this differs by sex.Methods: This study used data from 19184 UK Biobank participants aged 40-65 years. Diet quality was assessed using three dietary indices including the Mediterranean Diet Score (MDS), Healthy Diet Score (HDS), and Recommended Food Score (RFS). MRI brain measures included total, grey, white and hippocampal volume. Linear regression examined associations between diet quality and brain volume, controlling for potential confounders.Results: Better quality diet across all indices was significantly related to larger grey matter volume: MDS β= 429.7 (95%CI: 65.2, 794.2); HDS β= 700.1 (348.0, 1052.1); and RFS β= 317.1 (106.8, 527.3). Higher diet scores were associated with greater total volume: HDS β= 879.32 (286.13, 1472.50); RFS β= 563.37 (209.10, 917.65); and white matter volume: RFS β= 246.31 (20.56, 472.05), with the exception of Mediterranean diet adherence. Healthy eating guidelines and dietary variety associations with total and grey matter volume were more prominent in men.Conclusion: Findings suggest that diet quality is associated with brain structure during midlife, potentially decades prior to the onset of dementia. [ABSTRACT FROM AUTHOR]

Few neuroimaging studies are sufficiently large to adequately describe population‐wide variations. This study's primary aim was to generate neuroanatomical norms and individual markers that consider age, sex, and brain size, from 629 cerebral measures in the UK Biobank (N = 40,028). The secondary aim was to examine the effects and interactions of sex, age, and brain allometry—the nonlinear scaling relationship between a region and brain size (e.g., total brain volume)—across cerebral measures. Allometry was a common property of brain volumes, thicknesses, and surface areas (83%) and was largely stable across age and sex. Sex differences occurred in 67% of cerebral measures (median |β| =.13): 37% of regions were larger in males and 30% in females. Brain measures (49%) generally decreased with age, although aging effects varied across regions and sexes. While models with an allometric or linear covariate adjustment for brain size yielded similar significant effects, omitting brain allometry influenced reported sex differences in variance. Finally, we contribute to the reproducibility of research on sex differences in the brain by replicating previous studies examining cerebral sex differences. This large‐scale study advances our understanding of age, sex, and brain allometry's impact on brain structure and provides data for future UK Biobank studies to identify the cerebral regions that covary with specific phenotypes, independently of sex, age, and brain size. [ABSTRACT FROM AUTHOR]