Total Brain Volume Research Articles

Association of Metabolic Syndrome With Neuroimaging and Cognitive Outcomes in the UK Biobank.

Metabolic syndrome (MetS) has been linked to dementia. In this study, we examined the association of MetS with neuroimaging and cognition in dementia-free adults, offering insight into the impact of MetS on brain health prior to dementia onset. We included 37,395 dementia-free adults from the UK Biobank database. MetS was defined as having at least three of the following components: larger waist circumference; elevated levels of triglycerides, blood pressure, HbA1c; or reduced HDL cholesterol levels. Multivariable-adjusted linear regression was used to assess associations of MetS with structural neuroimaging and cognitive domains. MetS was associated with lower total brain (standardized β: -0.06; 95% CI -0.08, -0.04), gray matter (β: -0.10; 95% CI -0.12, -0.08) and hippocampal (for left side, β: -0.03, 95% CI -0.05, -0.01; for right side, β: -0.04, 95% CI -0.07, -0.02) volumes, and greater white matter hyperintensity (WMH) volume (β: 0.08; 95% CI 0.06, 0.11). Study participants with MetS performed poorer on cognitive tests of working memory (β: -0.10; 95% CI -0.13, -0.07), verbal declarative memory (β: -0.08; 95% CI -0.11, -0.05), processing speed (β: -0.06; 95% CI -0.09, -0.04), verbal and numerical reasoning (β: -0.07; 95% CI -0.09, -0.04), nonverbal reasoning (β: -0.03; 95% CI -0.05, -0.01), and on tests of executive function, where higher scores indicated poorer performance (β: 0.05; 95% CI 0.03, 0.08). More MetS components were also associated with less brain volume, greater WMH, and poorer cognition across all domains. MetS was associated poorer brain health in dementia-free adults, characterized by less brain volume, greater vascular pathology, and poorer cognition. Further research is necessary to understand whether reversal or improvement of MetS can improve brain health.

Childhood adiposity underlies numerous adult brain traits commonly attributed to midlife obesity.

Obese adults are often reported to have smaller brain volumes than their non-obese peers. Whether this represents evidence of accelerations in obesity-driven atrophy or is instead a legacy of developmental differences established earlier in the lifespan remains unclear. This study aimed to investigate whether early-life differences in adiposity explain differences in numerous adult brain traits commonly attributed to mid-life obesity. We utilised a two-sample lifecourse Mendelian randomization study in 37,501 adults recruited to UK Biobank (UKB) imaging centers from 2014, with secondary analyses in 6,996 children assessed in the Adolescent Brain Cognitive Development Study (ABCD) recruited from 2018. Exposures were genetic variants for childhood (266 variants) and adult (470 variants) adiposity derived from a GWAS of 407,741 UKB participants. Primary outcomes were adult total brain volume; grey matter volume, thickness, and surface area; white matter volume and hyperintensities; and hippocampus, amygdala, and thalamus volumes at mean age 55 in UKB. Secondary outcomes were equivalent childhood measures collected at mean age 10 in ABCD. In UKB, individuals who were genetically-predicted to have had higher levels of adiposity in childhood were found to have multiple smaller adult brain volumes relative to intracranial volume (e.g. z-score difference in normalised brain volume per category increase in adiposity [95%CI] = -0.20 [-0.28, -0.12]; p = 4 × 10-6). These effect sizes remained essentially unchanged after accounting for birthweight or current adult obesity in multivariable models, whereas most observed adult effects attenuated towards null (e.g. adult z-score [95%CI] for total volume = 0.06 [-0.05,0.17]; p = 0.3). Observational analyses in ABCD showed a similar pattern of changes already present in those with a high BMI by age 10 (z-score [95%CI] = -0.10 [-0.13, -0.07]; p = 8 × 10-13), with follow-up genetic risk score analyses providing some evidence for a causal effect already at this early age. Sensitivity analyses revealed that many of these effects were likely due to the persistence of larger head sizes established in those who gained excess weight in childhood (childhood z-score [95%CI] for intracranial volume = 0.14 [0.05,0.23]; p = 0.002), rather than smaller brain sizes per se. Our data suggest that persistence of early-life developmental differences across the lifecourse may underlie numerous neuroimaging traits commonly attributed to obesity-related atrophy in later life.

IMG-03. PRE-TREATMENT EVIDENCE OF ABNORMAL SUPRATENTORIAL WHITE MATTER IN CHILDREN WITH POSTERIOR FOSSA TUMOURS USING DIFFUSION MRI

Abstract BACKGROUND Over half of childhood brain tumours originate in the posterior fossa, which includes low-grade (e.g. pilocytic astrocytoma) and high-grade (e.g. medulloblastoma) tumours. Even though overall survival rates of paediatric brain tumours have substantially increased, survivors face neuropsychological impairments impacting behaviour, cognition, language and motor skills. Post-treatment outcomes are associated with structural changes within the brain, but it is unclear if observed microstructural damage is caused exclusively by radiotherapy or if there is earlier damage from the tumour and related effects. Diffusion MRI is a non-invasive technique that can be used to better understand white matter microstructure by quantifying water diffusion in the brain. Diffusion tensor imaging (DTI) can be used to assess white matter damage. METHODS In this work, we used DTI to understand white matter microstructure in 8 posterior fossa tumour patients prior to surgery. We compared individual patients to age- and sex-matched healthy controls in a one-against-many approach. RESULTS We demonstrate the presence of supratentorial white matter abnormalities prior to treatment in 3 patients. Before treatment, all patients are found to have significantly enlarged lateral ventricles relative to total brain volume (p<0.05). Patients with ventricle volumes >4% relative to brain volume correspond to significant changes in DTI parameters found in pre-treatment images, suggesting that hydrocephalus impacts white matter microstructure before surgery. Observed white matter changes are complex and patient-dependent, patients demonstrate compression (increased fractional anisotropy; FA) or diffuse oedema and damage (decreased FA). These white matter abnormalities persist over time, which could lead to cumulative damage, for example when adjuvant treatment involves radiotherapy. CONCLUSIONS To improve patient outcomes, pre-treatment imaging could be considered during individual treatment planning and risk evaluation to avoid further injury to white matter. Pre-treatment white matter abnormalities may have a bearing on neurocognitive patient outcomes, which will be the focus of future work.

Can gray matter loss in early adolescence be explained by white matter growth?

AbstractA fundamental puzzle about brain development is why the volume of gray matter (GM) apparently declines as white matter (WM) grows when children enter adolescence. Since pruned synapses are too small to affect GM volume, a prevailing theory posits that an expanded distribution of myelin causes the inner edge of the GM to “whiten” while total brain volume remains steady, shifting the MRI‐measured WM:GM boundary closer to the brain's outer surface. This theory inherently predicts that GM volume loss is concurrent with WM volume growth across regions, within sexes and over time, although these predictions have yet to be explicitly tested. In this study, we test these predictions by mapping regional GM and WM volumetric changes in 2333 participants of the Adolescent Brain Cognitive Development study aged 9–14 years who each received three MRI scans 2 years apart. We show that average GM and WM volume changes follow distinct spatial, temporal, and sex‐specific patterns, indicating that GM volume loss is not balanced by WM volume growth, although cortical GM thinning is weakly correlated with WM growth in some regions. We conclude that myelin is not the main source of measured GM volume loss, and we propose alternative candidates.

Long-term cognitive and brain morphologic changes in chronic heart failure: Results of the Cognition.Matters-HF study.

Cognitive impairment (CI) is a common, yet frequently unrecognized co-morbidity in chronic heart failure (HF). We quantified trajectories of cognitive performance, brain volume, and related clinical outcome over a time course of 6years. The Cognition.Matters-HF cohort study recruited patients with stable HF of any aetiology and severity. Beyond cardiological assessment, the workup included cognitive testing and brain magnetic resonance imaging (MRI). Of 148 recruited patients, 70% exhibited CI at baseline. During the median follow-up time of 69months (quartiles: 68, 70), indicators of HF severity remained essentially unaltered. CI was also stable, with the exception of intensity of attention, where age-adjusted t-scores decreased from 42 (38, 46) to 38 (34, 44; P<0.001). Complete sets of four serial brain MRI scans were available in 47 patients (32% of total sample). Total brain volume shrank by 0.4% per year, from 1103 (1060, 1143) cm3 to 1078 (1027, 1117) cm3, which was within limits observed in non-diseased ageing individuals. During follow-up, 29 study participants (20%) died, and 26 (18%) were at least once hospitalized due to worsening HF. The presence of CI was not associated with overall (P=0.290) or hospitalization-free (P=0.450) survival. In patients with stable HF patients receiving guideline-directed pharmacologic treatment and regular medical care, the presence of CI did not affect overall and hospitalization-free 6-year survival. The loss of brain parenchyma observed in patients with stable HF did not exceed that of normal ageing.

Gray matter volume mediates the association of long-term blood pressure variability with cognitive function in an adult population.

We delineated the associations among long-term blood pressure variability (BPV), brain structure, and cognitive function. We included 1254 adult participants from the Kailuan study. BPV was calculated from 2006 to 2020. Brain magnetic resonance imaging (MRI) and Montreal Cognitive Assessment (MoCA) were conducted in 2020. Higher systolic BPV (SBPV) and diastolic BPV (DBPV) were associated with lower total and frontal gray matter (GM) volume, and higher SBPV was associated with lower temporal GM volume. Elevated DBPV was associated with lower volume of total brain and parietal GM, and higher white matter hyperintensity (WMH) volume. Higher SBPV and DBPV were associated with lower MoCA scores. Decreased total and regional GM volume and increased WMH volume were associated with lower MoCA scores. The association between SBPV and cognitive function was mediated by total, frontal, and temporal GM volume. GM volume may play key roles in the association between SBPV and cognitive function. SBPV and DBPV were negatively associated with total and regional brain volume. SBPV and DBPV were negatively associated with cognitive function. Decreased brain volume was associated with cognitive decline. GM volume mediated the negative association between SBPV and cognitive function.

High Blood Pressure Is Associated With Lower Brain Volume and Cortical Thickness in Healthy Young Adults.

High blood pressure (BP) in middle-aged and older adults is associated with lower brain volume and cortical thickness assessed with structural magnetic resonance imaging (MRI). However, little evidence is available on young adults. We investigated the associations of high BP with brain volumes and cortical thickness in healthy young adults. This cross-sectional study included 1,095 young adults (54% women, 22-37 years) from the Human Connectome Project (HCP) who self-reported not having a history of hypertension or taking antihypertensive medications. Brachial systolic (SBP) and diastolic BP (DBP) were measured with a semi-automatic or manual sphygmomanometer during study visits. Structural MRI was used to measure gray matter (GM) and white matter (WM) volume and mean cortical thickness. Associations of BP and hypertension stage with total and regional brain volumes and cortical thickness were analyzed using linear regression and analysis of covariance (ANCOVA) after adjusting for age, sex, education years, body mass index (BMI), smoking, alcohol consumption history, zygosity, and total intracranial volume. SBP and DBP were (mean ± SD) 123.6 ± 14.2 and 76.5 ± 10.6 mm Hg, respectively, (n = 1,095). High DBP was associated with lower total GM (P = 0.012), cortical GM (P = 0.004), subcortical GM (P = 0.012), and total WM volumes (P = 0.031). High SBP and DBP were associated with lower regional cortical volume and cortical thickness. These findings suggest that high BP may have deleterious effects on brain health at the early stage of adulthood.

Comparative analysis of plan quality and delivery efficiency: ZAP-X vs. CyberKnife for brain metastases treatment

Purpose/ObjectivesZAP-X, a novel and dedicated radiosurgery (SRS) system, has recently emerged, while CyberKnife has solidified its position as a versatile solution for SRS and stereotactic body radiation therapy over the past two decades. This study aims to compare the dosimetric performance and delivery efficiency of ZAP-X and CyberKnife in treating brain metastases of varying target sizes, employing circular collimation.Methods and materialsTwenty-three patients, encompassing a total of 47 brain metastases, were included in the creation of comparative plans of ZAP-X and CyberKnife for analysis. The comparative plans were generated to achieve identical prescription doses for the targets, while adhering to the same dose constraints for organs at risk (OAR). The prescription isodose percentage was optimized within the range of 97–100% for each plan to ensure effective target-volume coverage. To assess plan quality, indices such as conformity, homogeneity, and gradient (CI, HI, and GI) were computed, along with the reporting of total brain volumes receiving 12Gy and 10Gy. Estimated treatment time and monitor units (MUs) were compared between the two modalities in evaluating delivery efficiency.ResultsOverall, CyberKnife achieved better CI and HI, while ZAP-X exhibited better GI and a smaller irradiated volume for the normal brain. The superiority of CyberKnife’s plan conformity was more pronounced for target size less than 1 cc and greater than 10 cc. Conversely, the advantage of ZAP-X’s plan dose gradient was more notable for target sizes under 10 cc. The homogeneity of ZAP-X plans, employing multiple isocenters, displayed a strong correlation with the target’s shape and the planner’s experience in placing isocenters. Generally, the estimated treatment time was similar between the two modalities, and the delivery efficiency was significantly impacted by the chosen collimation sizes for both modalities.ConclusionThis study demonstrates that, within the range of target sizes within the patient cohort, plans generated by ZAP-X and CyberKnife exhibit comparable plan quality and delivery efficiency. At present, with the current platform of the two modalities, CyberKnife outperforms ZAP-X in terms of conformity and homogeneity, while ZAP-X tends to produce plans with a more rapid dose falloff.

Volumetric study on sheep brain using stereology technique

AbstractThree‐dimensional morphometric data better show the structural and functional characteristics of the brain. The objective of this study was to estimate the volume of the cerebral structures of the sheep using design‐based stereology. The brains of five sheep were used, fixed in formalin 10% and embedded in agar 6%. An average of 10–12 slab was obtained from each brain. All slabs were stained using Mulligan's method and photographs were recorded. The volume of the brain and its structures were estimated using the Cavalieri's estimator and the point counting system. The total volume was 70604.8 ± 132.45 mm3. The volume fractions of the grey and white matters were calculated as 42.55 ± 0.21% and 24.23 ± 0.51% of the whole brain, respectively. The fractional volume of the caudate nucleus and claustrum were estimated at 2.39 ± 0.08% and at 1.008 ± 0.057% of total brain volume. The volumes of corpus callosum, internal capsule and external capsule were 1.24 ± 0.053%, 3.63 ± 0.22% and 0.698 ± 0.049% of total cerebral volume, respectively. These data could help improve the veterinary comparative neuroanatomy knowledge and development of experimental studies in the field.

A study on brain asymmetry in temporal lobe epilepsy

Objective: Temporal lobe epilepsy (TLE) accompanied by hippocampal sclerosis (HS) is the most common type of focal epilepsies. Hemispheric asymmetry is a feature of brain organization in both invertebrates and vertebrates and may be the key to some neurodegenerative diseases. In this context, we aimed to investigate the volumetric asymmetry difference in cerebral structures between TLE patients and the healthy control group, based on magnetic resonance imaging (MRI) data that may be used as a new neuroimaging marker for TLE cases. Patients and Methods: In this retrospective study the cranial MRIs of fourteen clinically manifesting, radiologically HS-identified, and diagnosed TLE patients and fourteen healthy individuals from the Radiology Department of Yeditepe University Hospital were evaluated. Volume measurements and asymmetry index (AI) calculations in the total brain, hippocampus, temporal lobe, amygdala, thalamus, nucleus accumbens (NAc), premotor cortex, primary and somatosensory cortices were performed using the medical NeuroQuant® software. A negative AI value represented asymmetry towards the right due to reduced left hemispheric volume; a positive AI value represented asymmetry towards the left due to reduced right hemispheric volume. Subsequently, differences in volume and asymmetric patterns were investigated among TLE subgroups (right and left-sided TLE) and controls. Results: The left-sided TLE patients showed significant bilateral total brain volume reduction compared to the control group. Significant ipsilateral volumetric declines were also detected in the premotor cortex, the temporal lobe, and NAc with remarkable asymmetry to the right side. No significant changes were detected in right-sided TLE patients compared to the other groups. Conclusion: Overall, findings suggest that TLE patients had volumetric alterations with symmetry changes beyond the mesial temporal structures. With further investigations, the asymmetry measures can provide additional knowledge for TLE diagnosis.

Lower activity of cholesteryl ester transfer protein (CETP) and the risk of dementia: a Mendelian randomization analysis

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): New Amterdam Pharma Background Elevated levels of low-density lipoprotein cholesterol (LDL-C) are linked to dementia risk, and conversely, increased plasma concentrations of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein-A1 (Apo-A1) associate with decreased dementia risk. Inhibition of cholesteryl ester transfer protein (CETP) meaningfully affects the concentrations of these blood lipids and may therefore provide an opportunity to treat dementia. Methods Drug target Mendelian randomization (MR) was employed to anticipate the on-target effects of lower CETP concentration (µg/mL) on plasma lipids, cardiovascular disease, Lewy body dementia (LBD), as well as Parkinson’s dementia. Replication was sought by performed Apo-A1 and Apo-B weighted MR analyses of CETP variants. Genetic associations with protein expression in cerebrospinal fluid (CSF) and brain were consulted to identify potential associations of plasma CETP with dementia implicated proteins. Results MR analysis of lower CETP concentration (per µg/mL) recapitulated the blood lipid effects observed in clinical trials of CETP-inhibitors, as well as protective effects on CHD (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.89; 0.96), heart failure, abdominal aortic aneurysm any stroke, ischemic stroke, and small vessel stroke (0.90, 95%CI 0.85; 0.96); Figure. Consideration of dementia related traits indicated that lower CETP concentrations were associated higher total brain volume (0.04 per standard deviation, 95%CI 0.02; 0.06), lower risk of LBD (OR 0.81, 95%CI 0.74; 0.89) and Parkinson’s dementia risk (OR 0.26, 95%CI 0.14; 0.48). APOE4 stratified analyses suggested the LBD effect was most pronounced in APOE-ε4+ participants (OR 0.61 95%CI 0.51; 0.73), compared to APOE-ε4- (OR 0.89 95%CI 0.79; 1.01); interaction p-value 5.81×10-4. The aforementioned associations were replicated using Apo-B and Apo-A1 weighted analyses; Figure. Additionally, MR was employed to link plasma CETP concentration to the levels of CSF and brain proteins such as EPHA2 and CSF-1, which are in development as dementia drug targets. Conclusion These results suggest that inhibition of CETP may be a viable strategy to treat dementia.

The heritability and structural correlates of resting-state fMRI complexity

The complexity of fMRI signals quantifies temporal dynamics of spontaneous neural activity, which has been increasingly recognized as providing important insights into cognitive functions and psychiatric disorders. However, its heritability and structural underpinnings are not well understood. Here, we utilize multi-scale sample entropy to extract resting-state fMRI complexity in a large healthy adult sample from the Human Connectome Project. We show that fMRI complexity at multiple time scales is heritable in broad brain regions. Heritability estimates are modest and regionally variable. We relate fMRI complexity to brain structure including surface area, cortical myelination, cortical thickness, subcortical volumes, and total brain volume. We find that surface area is negatively correlated with fine-scale complexity and positively correlated with coarse-scale complexity in most cortical regions, especially the association cortex. Most of these correlations are related to common genetic and environmental effects. We also find positive correlations between cortical myelination and fMRI complexity at fine scales and negative correlations at coarse scales in the prefrontal cortex, lateral temporal lobe, precuneus, lateral parietal cortex, and cingulate cortex, with these correlations mainly attributed to common environmental effects. We detect few significant associations between fMRI complexity and cortical thickness. Despite the non-significant association with total brain volume, fMRI complexity exhibits significant correlations with subcortical volumes in the hippocampus, cerebellum, putamen, and pallidum at certain scales. Collectively, our work establishes the genetic basis and structural correlates of resting-state fMRI complexity across multiple scales, supporting its potential application as an endophenotype for psychiatric disorders.

#1058 Causal discovery for the volume of white matter in patients undergoing haemodialysis

Abstract Background and Aims White matter hyperintensity is linked to adverse outcomes and a heightened risk of overt stroke and cognitive impairment, with its prevalence being more pronounced in patients undergoing haemodialysis than in the general population. Despite this, the determinants of white matter hyperintensity volume in patients undergoing haemodialysis remain unknown. Here, we aimed to utilise a statistical causal search approach to examine the factors influencing white matter hyperintensity volume, as measured by MRI, in patients undergoing haemodialysis. Method MRI measurements of white matter hyperintensity volumes were taken in 133 patients on outpatient maintenance haemodialysis for &amp;gt;1 year. Factors included in the statistical causal discovery model encompassed sex, underlying diseases that led to dialysis, total brain volume measured using MRI, and age and dialysis vintage at the time of MRI. Additionally, values calculated and averaged over the year before the MRI scan, such as pre-dialysis blood pressure, pulse, weight, blood pressure during dialysis, blood pressure after dialysis completion, the volume of water removed in one session, Kt/V, and URR and occurrences of sudden drops in blood pressure during dialysis, were considered. Missing measurements were supplemented using random forest. A statistical causal search using DirectLiNGAM was conducted, and clear temporal pre- and post-relationships were incorporated into the LiNGAM model as per prior knowledge. To enhance internal validity, 1000 bootstrap samplings were performed, and edges with a frequency of occurrence of ≥50% were considered valid for Directed Acyclic Graphs (DAGs). Factors directly linked to white matter volume were included in the model, and linear regression was executed. Results Patients had a mean age of 69.0 (Standard Deviation: 10.4) years, with 96 (72.2%) being male. The mean history of dialysis was 6.63 [Interquartile Range (IQR): 4.10, 10.78] years, and 40 (39.2%) patients had diabetes as the primary disease. The mean white matter hyperintensity volume was 14334.9 [IQR: 5262.4,30637.2]. Age, pre-dialysis body weight, post-dialysis mean blood pressure, and total brain volume were directly influenced by white matter volume. DAGs displaying causality obtained through bootstrapping are shown in the Fig. The regression model results revealed that white matter hyperintensity increased by 8376.3 [95% Confidence Intervals (CI): 4899.5 to 11853.1] for every 10 years of age, decreased by −2726.0 [95% CI: −4311.5 to −1140.5] with a 5 kg increase in pre-dialysis body weight, increased by 2089.7 [95% CI: 693.3 to 3540.0] with a 5-mmHg rise in post-dialysis mean blood pressure, and a 1 standard deviation increase in total cerebrum volume increased white matter volume by 13057.4 [95% CI: 8958.1 to 17156.8]. Conclusion The causal diagram indicated that age, pre-dialysis weight, post-dialysis mean blood pressure, and total cerebrum volume directly influenced white matter hyper intensity volume. The sudden drop in blood pressure during dialysis impacted white matter hyperintensity volume via post-dialysis mean blood pressure. Furthermore, age, post-dialysis mean blood pressure and total cerebrum volume had a facilitative effect on the increase in white matter hyperintensity volume, while pre-dialysis weight had a protective effect.

Sex-differences in the association of social health and marital status with blood-based immune and neurodegeneration markers in a cohort of community-dwelling older adults

BackgroundThe immune system has been proposed to play a role in the link between social health and all-cause dementia risk. We explored cross-sectional and longitudinal associations between social health, immune system balance and plasma neurodegeneration markers in community-dwelling older adults, and explored whether the balance between innate and adaptive immunity mediates associations between social health and both cognition and total brain volume. MethodsSocial health markers (social support, marital status, loneliness) were measured in the Rotterdam Study between 2002–2008. Immune system cell counts and balance were assessed repeatedly from 2002 to 2016 using white blood-cell-based indices and individual counts (granulocyte-to-lymphocyte ratio (GLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII)). Plasma neurodegeneration biomarkers (amyloid-β40, amyloid-β42, total tau and neurofilament light chain) were measured once from blood samples collected between 2002–2008. Global cognitive function and total brain volume (MRI) were measured at the follow-up visit between 2009–2014. We used linear mixed models to study longitudinal associations and performed causal mediation analyses. ResultsIn 8374 adults (mean age 65.7, 57 % female), never married participants (n = 394) had higher GLR, PLR and SII compared to married peers at baseline and during follow-up, indicating imbalance towards innate immunity. Being never married was associated with higher plasma amyloid-β40, and being widowed or divorced with higher plasma total tau levels at baseline. Widowed or divorced males, but not females, had higher GLR, PLR and SII at baseline. Higher social support was associated with lower PLR in females, but higher PLR in males. Loneliness was not associated with any of the immune system balance ratios. Never married males had higher levels of all plasma neurodegeneration markers at baseline. Immune system balance did not mediate associations between social health and cognition or total brain volume, but does interact with marital status. ConclusionThis study indicates that marital status is associated with blood-based immune system markers toward innate immunity and higher levels of plasma neurodegeneration markers. This is particularly evident for never married or previously married male older adults compared to married or female peers.

Life-course neighbourhood deprivation and brain structure in older adults: the Lothian Birth Cohort 1936.

Neighbourhood disadvantage may be associated with brain health but the importance of exposure at different stages of the life course is poorly understood. Utilising the Lothian Birth Cohort 1936, we explored the relationship between residential neighbourhood deprivation from birth to late adulthood, and global and local neuroimaging measures at age 73. A total of 689 participants had at least one valid brain measures (53% male); to maximise the sample size structural equation models with fullinformation maximum likelihood were conducted. Residing in disadvantaged neighbourhoods in mid- to late adulthood was associated with smaller total brain (β = -0.06; SE = 0.02; sample size[N] = 658; number of pairwise complete observations[n]=390), grey matter (β = -0.11; SE = 0.03; N = 658; n = 390), and normal-appearing white matter volumes (β = -0.07; SE = 0.03; N = 658; n = 390), thinner cortex (β = -0.14; SE = 0.06; N = 636; n = 379), and lower general white matter fractional anisotropy (β = -0.19; SE = 0.06; N = 665; n = 388). We also found some evidence on the accumulating impact of neighbourhood deprivation from birth to late adulthood on age 73 total brain (β = -0.06; SE = 0.02; N = 658; n = 276) and grey matter volumes (β = -0.10; SE = 0.04; N = 658; n = 276). Local analysis identified affected focal cortical areas and specific white matter tracts. Among individuals belonging to lower social classes, the brain-neighbourhood associations were particularly strong, with the impact of neighbourhood deprivation on total brain and grey matter volumes, and general white matter fractional anisotropy accumulating across the life course. Our findings suggest that living in deprived neighbourhoods across the life course, but especially in mid- to late adulthood, is associated with adverse brain morphologies, with lower social class amplifying the vulnerability.

Associations among plasma, MRI, and amyloid PET biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities in a community-dwelling cohort.

We evaluated associations between plasma and neuroimaging-derived biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities. We examined plasma biomarkers (neurofilament light chain, glial fibrillary acidic protein, amyloid beta [Aβ] 42/40, phosphorylated tau 181) and neuroimaging measures of amyloid deposition (Aβ-positron emission tomography [PET]), total brain volume, white matter hyperintensity volume, diffusion-weighted fractional anisotropy, and neurite orientation dispersion and density imaging free water. Participants were adjudicated as cognitively unimpaired (CU; N=299), mild cognitive impairment (MCI; N=192), or dementia (DEM; N=65). Biomarkers were compared across groups stratified by diagnosis, sex, race, and APOE ε4 carrier status. General linear models examined plasma-imaging associations before and after adjusting for demographics (age, sex, race, education), APOE ε4 status, medications, diagnosis, and other factors (estimated glomerular filtration rate [eGFR], body mass index [BMI]). Plasma biomarkers differed across diagnostic groups (DEM>MCI>CU), were altered in Aβ-PET-positive individuals, and were associated with poorer brain health and kidney function. eGFR and BMI did not substantially impact associations between plasma and neuroimaging biomarkers. Plasma biomarkers differ across diagnostic groups (DEM>MCI>CU) and are altered in Aβ-PET-positive individuals. Altered plasma biomarker levels are associated with poorer brain health and kidney function. Plasma and neuroimaging biomarker associations are largely independent of comorbidities.

Impaired polyamine metabolism causes behavioral and neuroanatomical defects in a mouse model of Snyder-Robinson syndrome.

Snyder-Robinson syndrome (SRS) is a rare X-linked recessive disorder caused by a mutation in the SMS gene, which encodes spermine synthase, and aberrant polyamine metabolism. SRS is characterized by intellectual disability, thin habitus, seizure, low muscle tone/hypotonia and osteoporosis. Progress towards understanding and treating SRS requires a model that recapitulates human gene variants and disease presentations. Here, we evaluated molecular and neurological presentations in the G56S mouse model, which carries a missense mutation in the Sms gene. The lack of SMS protein in the G56S mice resulted in increased spermidine/spermine ratio, failure to thrive, short stature and reduced bone density. They showed impaired learning capacity, increased anxiety, reduced mobility and heightened fear responses, accompanied by reduced total and regional brain volumes. Furthermore, impaired mitochondrial oxidative phosphorylation was evident in G56S cerebral cortex, G56S fibroblasts and Sms-null hippocampal cells, indicating that SMS may serve as a future therapeutic target. Collectively, our study establishes the suitability of the G56S mice as a preclinical model for SRS and provides a set of molecular and functional outcome measures that can be used to evaluate therapeutic interventions for SRS.

Cardiovascular disease risk exacerbates brain aging among Hispanic/Latino adults in the SOL-INCA-MRI Study.

Cardiovascular disease (CVD) risk factors are highly prevalent among Hispanic/Latino adults, while the prevalence of MRI infarcts is not well-documented. We, therefore, sought to examine the relationships between CVD risk factors and infarcts with brain structure among Hispanic/Latino individuals. Participants included 1,886 Hispanic/Latino adults (50-85 years) who underwent magnetic resonance imaging (MRI) as part of the Study of Latinos-Investigation of Neurocognitive Aging-MRI (SOL-INCA-MRI) study. CVD risk was measured approximately 10.5 years before MRI using the Framingham cardiovascular risk score, a measure of 10-year CVD risk (low (<10%), medium (10- < 20%), and high (≥20%)). MR infarcts were determined as present or absent. Outcomes included total brain, cerebral and lobar cortical gray matter, hippocampal, lateral ventricle, and total white matter hyperintensity (WMH) volumes. Linear regression models tested associations between CVD risk and infarct with MRI outcomes and for modifications by age and sex. Sixty percent of participants were at medium or high CVD risk. Medium and high CVD risk were associated with lower total brain and frontal gray matter and higher WMH volumes compared to those with low CVD risk. High CVD risk was additionally associated with lower total cortical gray matter and parietal volumes and larger lateral ventricle volumes. Men tended to have greater CVDRF-related differences in total brain volumes than women. The association of CVD risk factors on total brain volumes increased with age, equal to an approximate 7-year increase in total brain aging among the high-CVD-risk group compared to the low-risk group. The presence of infarct(s) was associated with lower total brain volumes, which was equal to an approximate 5-year increase in brain aging compared to individuals without infarcts. Infarcts were also associated with smaller total cortical gray matter, frontal and parietal volumes, and larger lateral ventricle and WMH volumes. The high prevalence of CVD risk among Hispanic/Latino adults may be associated with accelerated brain aging.

The impact of sunlight exposure on brain structural markers in the UK Biobank

Sunlight is closely intertwined with daily life. It remains unclear whether there are associations between sunlight exposure and brain structural markers. General linear regression analysis was used to compare the differences in brain structural markers among different sunlight exposure time groups. Stratification analyses were performed based on sex, age, and diseases (hypertension, stroke, diabetes). Restricted cubic spline was performed to examine the dose–response relationship between natural sunlight exposure and brain structural markers, with further stratification by season. A negative association of sunlight exposure time with brain structural markers was found in the upper tertile compared to the lower tertile. Prolonged natural sunlight exposure was associated with the volumes of total brain (β: − 0.051, P < 0.001), white matter (β: − 0.031, P = 0.023), gray matter (β: − 0.067, P < 0.001), and white matter hyperintensities (β: 0.059, P < 0.001). These associations were more pronounced in males and individuals under the age of 60. The results of the restricted cubic spline analysis showed a nonlinear relationship between sunlight exposure and brain structural markers, with the direction changing around 2 h of sunlight exposure. This study demonstrates that prolonged exposure to natural sunlight is associated with brain structural markers change.

Circulating sphingolipids and subclinical brain pathology: the cardiovascular health study.

Sphingolipids are implicated in neurodegeneration and neuroinflammation. We assessed the potential role of circulating ceramides and sphingomyelins in subclinical brain pathology by investigating their association with brain magnetic resonance imaging (MRI) measures and circulating biomarkers of brain injury, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the Cardiovascular Health Study (CHS), a large and intensively phenotyped cohort of older adults. Brain MRI was offered twice to CHS participants with a mean of 5 years between scans, and results were available from both time points in 2,116 participants (mean age 76 years; 40% male; and 25% APOE ε4 allele carriers). We measured 8 ceramide and sphingomyelin species in plasma samples and examined the associations with several MRI, including worsening grades of white matter hyperintensities and ventricular size, number of brain infarcts, and measures of brain atrophy in a subset with quantitative measures. We also investigated the sphingolipid associations with serum NfL and GFAP. In the fully adjusted model, higher plasma levels of ceramides and sphingomyelins with a long (16-carbon) saturated fatty acid were associated with higher blood levels of NfL [β = 0.05, false-discovery rate corrected P (PFDR) = 0.004 and β = 0.06, PFDR = < 0.001, respectively]. In contrast, sphingomyelins with very long (20- and 22-carbon) saturated fatty acids tended to have an inverse association with levels of circulating NfL. In secondary analyses, we found an interaction between ceramide d18:1/20:0 and sex (P for interaction = <0.001), such that ceramide d18:1/20:0 associated with higher odds for infarcts in women [OR = 1.26 (95%CI: 1.07, 1.49), PFDR = 0.03]. We did not observe any associations with GFAP blood levels, white matter grade, ventricular grade, mean bilateral hippocampal volume, or total brain volume. Overall, our comprehensive investigation supports the evidence that ceramides and sphingomyelins are associated with increased aging brain pathology and that the direction of association depends on the fatty acid attached to the sphingosine backbone.