Total Hippocampal Volume Research Articles

Association between hemoglobin levels and cerebral white matter volume in a general older Japanese population: the Iki-Iki study.

Although previous studies have reported that hemoglobin levels can affect the brain, very few have focused on the association between hemoglobin levels and brain volume. We aimed to identify the influence of hemoglobin levels on brain volume measured using magnetic resonance imaging (MRI) in a large elderly population. This cross-sectional study included 2153 participants (median age, 69 years; 60.2% female) who underwent 3T brain MRI. Multiple regression analyses were performed after adjusting for potential confounders. In the subgroup analyses, participants were divided into four groups according to sex and age threshold (lower age group [65-74] and higher age group [≥ 75]). After adjusting for potential confounders, total white matter volume reduction was found to be associated with decreased hemoglobin levels (females: standardized β = 0.059, [95% confidence interval (CI): 0.0032, 0.11], P = 0.038, males: standardized β = 0.069 [95% CI: -0.00023, 0.14], P = 0.051). This relationship was notable in younger age groups of both sexes. After adjustment, the total gray matter and hippocampal volumes were not significantly associated with hemoglobin levels. Low hemoglobin levels may have deleterious effects on white matter volume, which diminishes with age.

Effects of aerobic exercise on hippocampal formation volume in people with schizophrenia – a systematic review and meta-analysis with original data from a randomized-controlled trial

Abstract Background The hippocampal formation represents a key region in the pathophysiology of schizophrenia. Aerobic exercise poses a promising add-on treatment to potentially counteract structural impairments of the hippocampal formation and associated symptomatic burden. However, current evidence regarding exercise effects on the hippocampal formation in schizophrenia is largely heterogeneous. Therefore, we conducted a systematic review and meta-analysis to assess the impact of aerobic exercise on total hippocampal formation volume. Additionally, we used data from a recent multicenter randomized-controlled trial to examine the effects of aerobic exercise on hippocampal formation subfield volumes and their respective clinical implications. Methods The meta-analysis comprised six studies that investigated the influence of aerobic exercise on total hippocampal formation volume compared to a control condition with a total of 186 people with schizophrenia (100 male, 86 female), while original data from 29 patients (20 male, 9 female) was considered to explore effects of six months of aerobic exercise on hippocampal formation subfield volumes. Results Our meta-analysis did not demonstrate a significant effect of aerobic exercise on total hippocampal formation volume in people with schizophrenia (g = 0.33 [−0.12 to 0.77]), p = 0.15), but our original data suggested significant volume increases in certain hippocampal subfields, namely the cornu ammonis and dentate gyrus. Conclusions Driven by the necessity of better understanding the pathophysiology of schizophrenia, the present work underlines the importance to focus on hippocampal formation subfields and to characterize subgroups of patients that show neuroplastic responses to aerobic exercise accompanied by corresponding clinical improvements.

Neuroinflammation modifies the relationship between stress and perivascular spaces in an elderly population with different levels of cognitive impairment.

Perivascular spaces (PVS) are fluid-filled spaces surrounding the brain parenchymal vasculature. Literature suggests that PVS may play a significant role in aging and neurological disorders, including Alzheimer's disease (AD). The aim of this study is to investigate whether the relationship between MRI-visible PVS and stress is influenced by neuroinflammation in an elderly population with different levels of cognitive impairment. Using brain MRI scans acquired at 1.5 T, PVS were quantified in a cohort of 461 individuals, consisting of cognitively healthy controls (n = 48), people with mild cognitive impairment (MCI, n = 322) and Alzheimer's disease (AD, n = 91). PVS volume fraction was calculated in the basal ganglia and centrum semiovale using a semi-automated segmentation approach. Stress was quantified with levels of salivary cortisol. Inflammatory biomarkers measured from plasma included cytokines, matrix metalloproteinases and C-reactive protein. General linear models were used to test the relationship between PVS and cortisol, when interacting with inflammatory markers. This was done on the whole cohort and within each clinical cognitive group. In the centrum semiovale, higher inflammation levels reduced the relationship of cortisol with PVS. In basal ganglia, higher levels of C-reactive protein reduced the negative relationship of cortisol with PVS. All analyses were accounted for age, sex, body mass index (BMI) and total hippocampal volume. There was a significant interaction effect between cortisol and C-reactive protein on PVS volume fraction in the MCI group. These findings suggest an influence of neuroinflammation on the PVS structure in Alzheimer's disease spectrum, and offer insight for better understanding physiological processes of cognitive impairment onset.

Do total hippocampus and hippocampal subfield volumes relate to navigation ability? A call towards methodological consistency

Despite the need for successful navigation, humans vary greatly in their ability to navigate, and these individual differences may relate to variation in brain structure. While prior research provides support for a correlation between hippocampal volume and navigation ability in both navigation experts and in older individuals, this relationship is under scrutiny for healthy, young adults. We assessed 99 healthy young adults’ ability to navigate in a virtual, desktop maze and correlated their performance with total hippocampal gray matter volume. For a subset of these individuals, we further segmented the medial temporal lobe – including regions of the hippocampus – into anatomically-distinct subregions to uniquely examine the association between volumes of hippocampal subfields and navigation. Given the need to distinguish between similar-looking maze hallways and partially overlapping routes, young adults with stronger pattern separation ability may perform better in this task. Thus, we theorized that successful navigation would positively correlate with hippocampal CA3 and dentate gyrus (DG) subfield volumes due to these regions’ role in pattern separation. CA1 and entorhinal cortex (ERC) are both associated with rodent spatial memory, too, suggesting a possible relationship between their volumes and navigation performance. Consistent with our hypotheses, we observed a positive relationship between volumes of hippocampal subfields and wayfinding accuracy, while ERC and parahippocampal cortex volumes correlated with navigation efficiency. However, when analyzing total hippocampal volume, a nuanced interpretation is warranted. We found evidence of Simpson’s Paradox, where total hippocampal volume and navigation accuracy displayed no correlation in males, a negative correlation in females, yet a positive correlation when considering the full sample of males and females combined. Furthermore, no significant relationship was observed between total hippocampal volume and path efficiency. Given these findings, we urge caution in interpreting the results because these associations differ by analysis techniques (including voxel-based morphometry), after sex stratification, and with anterior and posterior hippocampal subdivisions. Overall, this study enhances our understanding of the relationship between brain volume and navigation ability for young adults but also emphasizes the need for methodological consistency across studies with respect to boundary definitions, neuroimaging techniques, statistical methods, and factors that give rise to individual differences.

Association of lamina cribrosa thickness and hippocampal volume in Alzheimer's disease patients.

Alzheimer's disease (AD) is the most common cause of dementia and affects a large portion of the elderly population worldwide. To analyze the relationship between lamina cribrosa thickness (LCT) and hippocampal volume in patients with AD and mild cognitive impairment (MCI). The sample in the present study consisted of 20 recently diagnosed MCI patients, 20 recently diagnosed AD patients, and 20 matched healthy volunteers. Every patient underwent magnetic resonance imaging (MRI) scans. The VolBrain software (open-access platform for MRI brain analysis) was used to calculate the hippocampal volume. Optical coherence tomography was performed to measure the LCT. Analysis of variance and Pearson chi-squared tests were employed to assess the results. The lowest total hippocampal volume (p < 0.05) was in the AD group, which was 6.14 ± 0.66 mm3, while in the control group, it was 7.7 ± 9.65 mm3, and 6.69 ± 0.46 mm3 in the MCI group. In comparison to the rest of the groups, in the AD group, the LCT was the thinnest (202.17 ± 16.35 µm). As per the results of the study population as a whole, low hippocampal volume causes low LCT, which shows an important relationship (r: 0.41; p < 0.05). The current findings present evidence of the relationship between hippocampal volume and LCT in patients with AD and MCI.

It takes three: Parental hostility, brain morphology and child externalizing problems in a parent-offspring neuroimaging trio design.

Hostility often co-occurs in parents and associates with increased aggression and inattention problems in children. In this population-based cohort of 484 mother-father-child neuroimaging trios, we investigated the degree to which associations of prenatal and childhood parental hostility would be associated with maternal, paternal and child brain structural differences. Also, we examined whether hippocampal volumes of the parents or child mediate the association of prenatal parental hostility with child externalizing behaviors. Maternal and paternal hostility was assessed with the hostility subscale of the Brief-Symptom-Inventory at three time points: prenatally at 30 weeks gestation, and when the child was 3 and 10 years old. During adolescence assessment wave (age 14), maternal, paternal, and offspring assessment included a magnetic-resonance-imaging (MRI). Child externalizing problems were assessed with Youth-Self-Report-Child-Behavior-Checklist.Our findings suggest that maternal and paternal hostility were each associated with smaller gray matter, white matter, and hippocampal volumes of their own and their partner's brain. Prenatal maternal but not paternal hostility was associated with smaller total gray matter, white matter, and hippocampal volumes in the offspring. The child's hippocampal volumes partially mediated the associations of prenatal parental hostility (latent-construct) with adolescent externalizing behavior, even after adjusting for prior child externalizing problems. Moreover, parental psychopathology may have long-lasting neurodevelopmental correlates in children that underlie the intergenerational transmission of behavioral problems. The behavior of family members results from a system of interdependent dyadic relationships over time that associate with specific brain structural differences.Significance statement Parental hostility often co-occurs in the parents. Research suggests that what transpires in one family subsystem, e.g. hostility among parents, is related to what transpires in other subsystems, e.g. mother-child or father-child, and can negatively impact child development. To understand the neurobiological effects of parental hostility on the families, these can best be studied with trio analysis as parents and children may all be affected. Overall, the findings elucidate how hostility of a parent negatively relates to different family subsystems and associated brain characteristic, such as the hippocampal volume. Our findings suggest that the behavior of family members results from a system of interdependent dyadic relationships over time that associate with specific brain structural differences.

Sex differences in association between dietary sodium intake and white matter hyperintensity volume

Abstract Background There is limited evidence on the relationship between dietary sodium intake (dNa) and brain health, and very little on sex differences in associations. Purpose To study the relationship between dNa and imaging measures of brain health in men and women from the INSIGHT 46 substudy of the MRC National Survey of Health and Development (British 1946 birth cohort). Methods Participants had measurements (dNa using 5-day food diary, anthropometrics, blood pressure (BP) body mass index (BMI)) at 60-64years. Whole-brain and hippocampal volumes, white matter hyperintensity volume (WMHV) and florbetapir amyloid-β positivity were measured using MRI-PET imaging at 69-71years. Associations (β (95% confidence intervals)) were estimated separately in men and women using generalized linear models with robust standard errors adjusted for potential confounders (age, diet quality, energy intake, socioeconomic status) or potential mediators (BMI, BP). Results Participants’ characteristics are shown in Table 1. In women but not men dNa was positively associated with higher WMHV (β[women]=32(1, 72) %/g; p=0.043; β[men]=-10(-27, 11)%/g; p=0.342); this relationship in women was independent of BMI (β = 32(1, 72)%/g; p = 0.043) or systolic BP (β = 31(1, 70)%/g; p=0.041). dNa was not associated with total brain volume, hippocampal volume or amyloid-β positivity in either sex. Conclusions Elevated sodium consumption in the diet is associated with cerebral small vessel disease in older age women but not men. This association was independent of BMI or BP.Table 1

Hippocampal volumes in UK Biobank are associated with APOE only in older adults.

The hippocampus atrophies with age and is implicated in neurodegenerative disorders including Alzheimer's disease (AD). We examined the interplay between age and apolipoprotein E (APOE) genotype on total hippocampal volume. Using neuroimaging data from 37,463 UK Biobank participants, we applied linear regression to quantify the association of age and APOE with hippocampal volume and identified the age when volumes of ε2/ε3, ε3/ε4, and ε4/ε4 carriers significantly deviated from ε3/ε3 using generalized additive modeling. Total hippocampal volume declined with age, with significant differences by APOE genotype emerging after age 60. ε3/ε4 and ε4/ε4 carriers displayed reduced volumes from ages 69 and 61, respectively, while ε2/ε3 showed delayed decline starting at the age of 76. The association of APOE and hippocampal volume is age-dependent, with differences in volumes of ε4/ε4 carriers detected as early as age 61. This work underscores the importance of APOE genotype in determining when to begin screening for AD. Apolipoprotein E (APOE) genotype shows an age-dependent association with total hippocampal volume.No association between APOE and total hippocampal volume was detected before age 60.Accelerated decline was observed in ε4/ε4 carriers at age 61 and ε3/ε4 at age 69.Delayed decline was evident in ε2/ε3 carriers starting at age 76.

Interactions between muscle volume and body mass index on brain structure in the UK Biobank.

Low skeletal muscle volume may increase dementia risk through mechanisms affecting brain structure. However, it is unclear whether this relationship exists outside of sarcopenia and/or varies by other factors. We aimed to study the interplay between skeletal muscle volume and factors, such as age, sex, and body mass index (BMI), in explaining brain structure at midlife in a cohort without sarcopenia. We used abdominal and brain magnetic resonance imaging (MRI) data from a population-based cohort enrolled in the UK Biobank. The following measures were derived: thigh fat-free muscle volume (FFMV), total brain volume (TBV), gray matter volume (GMV), white matter volume (WMV), total hippocampal volume (THV), and white matter hyperintensity volume (WMHV). Participants below sex-based grip strength thresholds suggesting probable sarcopenia were excluded. Linear regression analysis was used to study the interaction or mediation effects of age, sex, and BMI on the associations between FFMV and brain volumes. Data were available for 20,353 participants (median age 64 years, 53% female). We found interactions between thigh FFMV, BMI, and age (all p < 0.05). Greater thigh FFMV was associated with better brain volumes in those aged <64 years with normal (TBV: β = 2.0 ml/L, p = 0.004; GMV: β = 0.8 ml/L, p = 0.04; WMV: β = 1.1 ml/L, p = 0.006; WMHV: β = -0.2 ml/L, p = 3.7 × 10-5) or low BMI (TBV: β = 21.2 ml/L, p = 0.003; WMV: β = 13.3 ml/L, p = 0.002, WMHV: β = -1.1 ml/L, p = 0.04). Greater thigh muscle volume correlates with better brain volumes at midlife in people without sarcopenia, but this relationship weakens with greater age and BMI. Further study is required to investigate the underlying mechanisms to understand which components of body composition are potentially modifiable risk factors for dementia.

Effects of glycaemic control on memory performance, hippocampal volumes and depressive symptomology

BackgroundDiabetes and poor glycaemic control have been shown to negatively impact cognitive abilities, while also raising risk of both mood disorders and brain structural atrophy. Sites of atrophy include the hippocampus, which has been implicated in both memory performance and depression. The current study set out to better characterise the associations between poor glycaemic control, memory performance, and depression symptoms, and investigate whether loss of hippocampal volume could represent a neuropathological mechanism underlying these.Methods1331 participants (60.9% female, age range 18–88 (Mean = 44.02), 6.5% with likely diabetes) provided HbA1c data (as an index of glycaemic control), completed a word list learning task, and a validated depression scale. A subsample of 392 participants underwent structural MRI; hippocampal volumes were extracted using FreeSurfer.ResultsPartial correlation analyses (controlling for age, gender, and education) showed that, in the full sample, poorer glycaemic control was related to lower word list memory performance. In the MRI sub-sample, poorer glycaemic control was related to higher depressive symptoms, and lower hippocampal volumes. Total hippocampus volume partially mediated the association between HbA1c levels and depressive symptoms.ConclusionsResults emphasise the impact of glycaemic control on memory, depression and hippocampal volume and suggest hippocampal volume loss could be a pathophysiological mechanism underlying the link between HbA1c and depression risk; inflammatory and stress-hormone related processes might have a role in this.

Predicting Cognitive Decline in Amyloid-Positive Patients With Mild Cognitive Impairment or Mild Dementia.

Cognitive decline rates in Alzheimer disease (AD) vary greatly. Disease-modifying treatments may alter cognitive decline trajectories, rendering their prediction increasingly relevant. We aimed to construct clinically applicable prediction models of cognitive decline in amyloid-positive patients with mild cognitive impairment (MCI) or mild dementia. From the Amsterdam Dementia Cohort, we selected amyloid-positive participants with MCI or mild dementia and at least 2 longitudinal Mini-Mental State Examination (MMSE) measurements. Amyloid positivity was based on CSF AD biomarker concentrations or amyloid PET. We used linear mixed modeling to predict MMSE over time, describing trajectories using a cubic time curve and interactions between linear time and the baseline predictors age, sex, baseline MMSE, APOE ε4 dose, CSF β-amyloid (Aβ) 1-42 and pTau, and MRI total brain and hippocampal volume. Backward selection was used to reduce model complexity. These models can predict MMSE over follow-up or the time to an MMSE value. MCI and mild dementia were modeled separately. Internal 5-fold cross-validation was performed to calculate the explained variance (R2). In total, 961 participants were included (age 65 ± 7 years, 49% female), 310 had MCI (MMSE 26 ± 2) and 651 had mild dementia (MMSE 22 ± 4), with 4 ± 2 measurements over 2 (interquartile range 1-4) years. Cognitive decline rates increased over time for both MCI and mild dementia (model comparisons linear vs squared vs cubic time fit; p < 0.05 favoring a cubic fit). For MCI, backward selection retained age, sex, and CSF Aβ1-42 and pTau concentrations as time-varying effects altering the MMSE trajectory. For mild dementia, retained time-varying effects were Aβ1-42, age, APOE ε4, and baseline MMSE. R2 was 0.15 for the MCI model and 0.26 for mild dementia in internal cross-validation. A hypothetical patient with MCI, baseline MMSE 28, and CSF Aβ1-42 of 925 pg/mL was predicted to reach an MMSE of 20 after 6.0 years (95% CI 5.4-6.7) and after 8.6 years with a hypothetical treatment reducing decline by 30%. We constructed models for MCI and mild dementia that predict MMSE over time. These models could inform patients about their potential cognitive trajectory and the remaining uncertainty and aid in conversations about individualized potential treatment effects.

Hippocampus and olfactory impairment in Parkinson disease: a comparative exploratory combined volumetric/functional MRI study.

Patients with Parkinson's Disease (PD) commonly experience Olfactory Dysfunction (OD). Our exploratory study examined hippocampal volumetric and resting-state functional magnetic resonance imaging (rs-fMRI) variations in a Healthy Control (HC) group versus a cognitively normal PD group, further categorized into PD with No/Mild Hyposmia (PD-N/MH) and PD with Severe Hyposmia (PD-SH). We calculated participants' relative Total Hippocampal Volume (rTHV) and performed Spearman's partial correlations, controlled for age and gender, to examine the correlation between rTHV and olfactory performance assessed by the Odor Stick Identification Test for the Japanese (OSIT-J) score. Mann-Whitney U tests assessed rTHV differences across groups and subgroups, rejecting the null hypothesis for p < 0.05. Furthermore, a seed-based rs-fMRI analysis compared hippocampal connectivity differences using a one-way ANCOVA covariate model with controls for age and gender. Spearman's partial correlations indicated a moderate positive correlation between rTHV and OSIT-J in the whole study population (ρ = 0.406; p = 0.007), PD group (ρ = 0.493; p = 0.008), and PD-N/MH subgroup (ρ = 0.617; p = 0.025). Mann-Whitney U tests demonstrated lower rTHV in PD-SH subgroup compared to both HC group (p = 0.013) and PD-N/MH subgroup (p = 0.029). Seed-to-voxel rsfMRI analysis revealed reduced hippocampal connectivity in PD-SH subjects compared to HC subjects with a single cluster of voxels. Although the design of the study do not allow to make firm conclusions, it is reasonable to speculate that the progressive involvement of the hippocampus in PD patients is associated with the progression of OD.

Exploring the cognitive assessment potential of MRI-based volumetric hippocampal segmentation in Parkinson's disease.

To investigate the potential of magnetic resonance imaging (MRI)-based total and segmental hippocampus volume analysis in the assessment of cognitive status in Parkinson's disease (PD). We divided participants into three groups Group A-Parkinson patients (Pp) with normal cognitive status (n=25), Group B-Pp with dementia (n=17), and Group C-healthy controls (n=37). Three-dimensional T1W Fast Spoiled Gradient Recalled Echo images were used for Volbrain hippocampus subfield segmentation. We used the "Winterburn" protocol, which divides the hippocampus into five segments, Cornu Ammonis (CA),CA2/CA3, CA4/dentate gyrus, stratum radiatum, lacunosum, and moleculare, and subiculum. A total of 79 participants were included in the study, consisting of 42 individuals with PD (64.2% male) and 37 healthy controls (54.1% male). The mean age of PD was 60.9±10.7 years and the mean age of control group was 59.27±12.3 years. Significant differences were found in total hippocampal volumes between Group A and B (p=.047. Statistically significant group differences were found in total, right, and left CA1 volumes (analysis of variance [ANOVA]: F(2,76)=8.098, p=.001; F(2,76)=7.628, p=.001; F(2,76)=5.084, p=.008, respectively), as well as in total subiculum volumes (ANOVA: F(2,76)=4.368, p=.016). Post hoc tests showed that total subiculum volume was significantly lower in individuals with normal cognitive status (0.474±0.116cm3) compared to healthy controls (0.578±0.151cm3, p=.013). Volumetric hippocampal MRI can be used to assess the cognitive status of Pp. Longitudinal studies that evaluate Pp who progress from normal cognition to dementia are required to establish a causal relationship.

Childhood blood-lead level predicts lower general, non-selective hippocampal subfield volumes in midlife

Millions of adults and children are exposed to high levels of lead, a neurotoxicant, each year. Recent evidence suggests that lead exposure may precipitate neurodegeneration, particularly if the exposure occurs early or late in life, with unique alterations to the structure or function of specific subfields of the hippocampus, a region involved in memory and Alzheimer’s disease. It has been proposed that specific hippocampal subfields may thus be useful biomarkers for lead-associated neurological disease. We turned to a population-representative New Zealand birth cohort where the extent of lead exposure was not confounded by social class (the Dunedin Study; born 1972–1973 and followed to age 45) to test the hypothesis that early life lead exposure (blood-lead level at age 11 years) is associated with smaller MRI-assessed gray matter volumes of specific subfields of the hippocampus at age 45 years. Among the 508 Dunedin Study members with childhood lead data and adult MRI data passing quality control (93.9 % of those with lead data who attended the age-45 assessment wave, 240[47.2 %] female), childhood blood-lead levels ranged from 4 to 31 µg/dL (M[SD]=10.9[4.6]). Total hippocampal volumes were lower among adults with higher childhood blood-lead levels (b=-102.6 mm3 per 5 ug/dL-unit greater blood-lead level, 95 %CI: −175.4 to −29.7, p=.006, β=-.11), as were all volumes of the 24 hemisphere-specific subfields of the hippocampus. Of these 24 subfields, 20 demonstrated negative lead-associations greater than β=-.05 in size, 14 were statistically significant after adjustment for multiple comparisons (pFDR<.05), and 9 remained significant after adjustment for potential confounders and multiple comparisons. Children exposed to lead demonstrate smaller volumes across all subfields of the hippocampus in midlife. The hypothesis that lead selectively impairs specific subfields of the hippocampus, or that specific subfields may be markers for lead-associated neurological disease, requires further evaluation.

Interactions between age, sex and visceral adipose tissue on brain ageing.

To examine the associations between visceral adipose tissue (VAT) and brain structural measures at midlife and explore how these associations may be affected by age, sex and cardiometabolic factors. We used abdominal and brain magnetic resonance imaging data from a population-based cohort of people at midlife in the UK Biobank. Regression modelling was applied to study associations of VAT volume with total brain volume (TBV), grey matter volume (GMV), white matter volume, white matter hyperintensity volume (WMHV) and total hippocampal volume (THV), and whether these associations were altered by age, sex or cardiometabolic factors. Complete data were available for 17 377 participants (mean age 63 years, standard deviation = 12, 53% female). Greater VAT was associated with lower TBV, GMV and THV (P < .001). We found an interaction between VAT and sex on TBV (P < .001), such that the negative association of VAT with TBV was greater in men (β = -2.89, 95% confidence interval [CI] -2.32 to -10.15) than in women (β = -1.32, 95% CI -0.49 to -3.14), with similar findings for GMV. We also found an interaction between VAT and age (but not sex) on WMHV (P < .001). The addition of other cardiometabolic factors or measures of physical activity resulted in little change to the models. VAT volume is associated with poorer brain health in midlife and this relationship is greatest in men and those at younger ages.

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.

Hippocampal volumes in UK Biobank are associated with APOE only in older adults.

The hippocampus atrophies with age and is implicated in neurodegenerative disorders including Alzheimer's disease (AD). We examined the interplay between age and APOE genotype on total hippocampal volume. Utilizing neuroimaging data from 37,463 UK Biobank participants, we applied linear regression to quantify the association of age and APOE with hippocampal volume and identified the age when volumes of ε2/ε3, ε3/ε4, and ε4/ε4 carriers significantly deviated from ε3/ε3 using generalized additive modeling. Total hippocampal volume declined with age, with significant differences by APOE genotype emerging after age 60. ε3/ε4 and ε4/ε4 carriers displayed reduced volumes from ages 69 and 61, respectively, while ε2/ε3 showed delayed decline starting at age 76. The association of APOE and hippocampal volume is age-dependent, with differences in volumes of ε4/ε4 carriers detected as early as age 61. This work underscores the importance of APOE genotype in determining when to begin screening for AD.

Short-Term Practice Effects on Cognitive Tests Across the Late Life Cognitive Spectrum and How They Compare to Biomarkers of Alzheimer's Disease.

Practice effects on cognitive testing in mild cognitive impairment (MCI) and Alzheimer's disease (AD) remain understudied, especially with how they compare to biomarkers of AD. The current study sought to add to this growing literature. Cognitively intact older adults (n = 68), those with amnestic MCI (n = 52), and those with mild AD (n = 45) completed a brief battery of cognitive tests at baseline and again after one week, and they also completed a baseline amyloid PET scan, a baseline MRI, and a baseline blood draw to obtain APOE ɛ4 status. The intact participants showed significantly larger baseline cognitive scores and practice effects than the other two groups on overall composite measures. Those with MCI showed significantly larger baseline scores and practice effects than AD participants on the composite. For amyloid deposition, the intact participants had significantly less tracer uptake, whereas MCI and AD participants were comparable. For total hippocampal volumes, all three groups were significantly different in the expected direction (intact > MCI > AD). For APOE ɛ4, the intact had significantly fewer copies of ɛ4 than MCI and AD. The effect sizes of the baseline cognitive scores and practice effects were comparable, and they were significantly larger than effect sizes of biomarkers in 7 of the 9 comparisons. Baseline cognition and short-term practice effects appear to be sensitive markers in late life cognitive disorders, as they separated groups better than commonly-used biomarkers in AD. Further development of baseline cognition and short-term practice effects as tools for clinical diagnosis, prognostic indication, and enrichment of clinical trials seems warranted.

The Association between Dietary Protein Intake and Sources and the Rate of Longitudinal Changes in Brain Structure.

Few studies have examined dietary protein intake and sources, in combination with longitudinal changes in brain structure markers. Our study aimed to examine the association between dietary protein intake and different sources of dietary protein, with the longitudinal rate of change in brain structural markers. A total of 2723 and 2679 participants from the UK Biobank were separately included in the analysis. The relative and absolute amounts of dietary protein intake were calculated using a 24 h dietary recall questionnaire. The longitudinal change rates of brain structural biomarkers were computed using two waves of brain imaging data. The average interval between the assessments was three years. We utilized multiple linear regression to examine the association between dietary protein and different sources and the longitudinal changes in brain structural biomarkers. Restrictive cubic splines were used to explore nonlinear relationships, and stratified and sensitivity analyses were conducted. Increasing the proportion of animal protein in dietary protein intake was associated with a slower reduction in the total hippocampus volume (THV, β: 0.02524, p < 0.05), left hippocampus volume (LHV, β: 0.02435, p < 0.01) and right hippocampus volume (RHV, β: 0.02544, p < 0.05). A higher intake of animal protein relative to plant protein was linked to a lower atrophy rate in the THV (β: 0.01249, p < 0.05) and LHV (β: 0.01173, p < 0.05) and RHV (β: 0.01193, p < 0.05). Individuals with a higher intake of seafood exhibited a higher longitudinal rate of change in the HV compared to those that did not consume seafood (THV, β: 0.004514; p < 0.05; RHV, β: 0.005527, p < 0.05). In the subgroup and sensitivity analyses, there were no significant alterations. A moderate increase in an individual's intake and the proportion of animal protein in their diet, especially from seafood, is associated with a lower atrophy rate in the hippocampus volume.

Association of Regular Opioid Use With Incident Dementia and Neuroimaging Markers of Brain Health in Chronic Pain Patients: Analysis of UK Biobank

ObjectivesWe aimed to investigate the association of regular opioid use, compared with non-opioid analgesics, with incident dementia and neuroimaging outcomes among chronic pain patients. DesignThe primary design is a prospective cohort study. To triangulate evidence, we also conducted a nested case-control study analyzing opioid prescriptions and a cross-sectional study analyzing neuroimaging outcomes. Setting and ParticipantsDementia-free UK Biobank participants with chronic pain and regular analgesic use. MeasurementsChronic pain status and regular analgesic use were captured using self-reported questionnaires and verbal interviews. Opioid prescription data were obtained from primary care records. Dementia cases were ascertained using primary care, hospital, and death registry records. Propensity score-matched Cox proportional hazards analysis, conditional logistic regression, and linear regression were applied to the data in the prospective cohort, nested case-control, and cross-sectional studies, respectively. ResultsProspective analyses revealed that regular opioid use, compared with non-opioid analgesics, was associated with an increased dementia risk over the 15-year follow-up (Hazard ratio [HR], 1.18 [95% confidence interval (CI): 1.08–1.30]; Absolute rate difference [ARD], 0.44 [95% CI: 0.19–0.71] per 1000 person-years; Wald χ2 = 3.65; df = 1; p <0.001). The nested case-control study suggested that a higher number of opioid prescriptions was associated with an increased risk of dementia (1 to 5 prescriptions: OR = 1.21, 95% CI: 1.07–1.37, Wald χ2 = 3.02, df = 1, p = 0.003; 6 to 20: OR = 1.27, 95% CI: 1.08–1.50, Wald χ2 = 2.93, df = 1, p = 0.003; more than 20: OR = 1.43, 95% CI: 1.23–1.67, Wald χ2 = 4.57, df = 1, p < 0.001). Finally, neuroimaging analyses revealed that regular opioid use was associated with lower total grey matter and hippocampal volumes, and higher white matter hyperintensities volumes. ConclusionRegular opioid use in chronic pain patients was associated with an increased risk of dementia and poorer brain health when compared to non-opioid analgesic use. These findings imply a need for re-evaluation of opioid prescription practices for chronic pain patients and, if further evidence supports causality, provide insights into strategies to mitigate the burden of dementia.