Sex differences in brain aging and predictors of neurodegeneration in cognitively healthy older adults.
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ABSTRACT:
SUBMITTER: Armstrong NM
PROVIDER: S-EPMC9310670 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Effects of Alzheimer's disease (AD) risk factors on brain volume changes may partly explain what happens during the preclinical AD stage in people who develop subsequent cognitive impairment (SI). We investigated predictors of neurodegeneration, measured by MRI-based volume loss, in older adults before diagnosis of cognitive impairment. There were 623 cognitively normal and 65 SI Baltimore Longitudinal Study of Aging participants (age 55-92 years) enrolled in the neuroimaging substudy from 1994 to 2015. Mixed-effects regression was used to assess the associations of AD risk factors (age, APOE e4 carrier status, diabetes, hypertension, obesity, current smoking, and elevated cholesterol) with brain regional volume change among the overall sample and by diagnostic status. Older age, APOE e4 carrier status, hypertension, and HDL cholesterol were predictors of volumetric change. Among SI participants only, hypertension, obesity, and APOE e4 carrier status were associated with greater declines in selected brain regions. SI individuals in the preclinical AD stage are vulnerable to risk factors that have either a protective or null effect in cognitively normal individuals.
| S-EPMC6394867 | biostudies-literature
Project description:OBJECTIVE:Amyloid positivity is a biomarker of AD pathology, yet the associations between amyloid positivity and brain volumetric changes, especially in the hippocampus, are inconsistent. We hypothesize that sex differences in associations may contribute to inconsistent findings among cognitively normal older adults. METHODS:Using linear mixed effects models, we examined the association of amyloid positivity with prospective volumetric changes (mean = 3.3 visits) of parahippocampal gyrus (phg), hippocampus, entorhinal cortex (erc), precuneus, and fusiform gyrus among 171 Baltimore Longitudinal Study of Aging participants aged ≥55 years. Amyloid positivity was defined by a mean 11C-Pittsburgh Compound B (PiB) distribution volume ratio (DVR) cut-off of 1.062. All analyses included age, race, sex, education, APOE e4 carrier status, and two-way interactions of these covariates with time. Two-way interaction between sex and PiB+/- status and three-way interaction of sex and PiB+/- status with time were added to assess whether sex modified associations. RESULTS:PiB+ status was associated with greater volumetric declines in the phg (β = -0.036, SE = 0.011, p = 0.001) and erc (β = -0.019, SE = 0.009, p = 0.045). Sex modified the association of PiB+ status and rates of volumetric declines in fusiform (β = -0.117, SE = 0.049, p = 0.019). PiB+ males had steeper rates of volumetric declines in phg (β = -0.051, SE = 0.013, p < 0.001) and erc (β = -0.029, SE = 0.012, p = 0.014) than PiB- males, while there was no difference in rates of volumetric change between PiB+ and PiB- females. CONCLUSIONS:Amyloidosis is a marker of entorhinal and parahippocampal volume loss. Amyloid positivity is a predictor of volume loss in brain regions affected by early AD pathology in men, but not women.
| S-EPMC6444285 | biostudies-literature
Project description:IntroductionLate onset Alzheimer's disease (AD) is the most common form of dementia, in which almost 70% of patients are women.HypothesisWe hypothesized that women show worse global FC metrics compared to men, and further hypothesized a sex-specific positive correlation between FC metrics and cognitive scores in women.MethodsWe studied cognitively healthy individuals from the Alzheimer's Disease Neuroimaging Initiative cohort, with resting-state functional Magnetic Resonance Imaging. Metrics derived from graph theoretical analysis and functional connectomics were used to assess the global/regional sex differences in terms of functional integration and segregation, considering the amyloid status and the contributions of APOE E4. Linear mixed effect models with covariates (education, handedness, presence of apolipoprotein [APOE] E4 and intra-subject effect) were utilized to evaluate sex differences. The associations of verbal learning and memory abilities with topological network properties were assessed.ResultWomen had a significantly lower magnitude of the global and regional functional network metrics compared to men. Exploratory association analysis showed that higher global clustering coefficient was associated with lower percent forgetting in women and worse cognitive scores in men.ConclusionWomen overall show lower magnitude on measures of resting state functional network topology and connectivity. This factor can play a role in their different vulnerability to AD.Significance statementTwo thirds of AD patients are women but the reasons for these sex difference are not well understood. When this late onset form dementia arises is too late to understand the potential causes of this sex disparities. Studies on cognitively healthy elderly population are a fundamental approach to explore in depth this different vulnerability to the most common form of dementia, currently affecting 6.2 million Americans aged 65 and older are, which means that >1 in 9 people (11.3%) 65 and older are affected by AD. Approaches such as resting-state functional network topology and connectivity may play a key role in understanding and elucidate sex-dependent differences relevant to late-onset dementia syndromes.
| S-EPMC9252274 | biostudies-literature
Project description:Biomarkers associated with Alzheimer's disease (AD)-like brain atrophy in healthy individuals may identify mechanisms involved in early stage AD. Aside from cerebrospinal fluid (CSF) ?-amyloid42 (A?42) and tau, no studies have tested associations between CSF proteins and AD-like brain atrophy. We studied 90 healthy elders, who underwent lumbar puncture at baseline, and serial magnetic resonance imaging scans for up to 4 years. We tested statistical effects of baseline CSF proteins (N = 70 proteins related to A?42-metabolism, microglial activity, and synaptic/neuronal function) on atrophy rates in 7 AD-related regions. Besides the effects of A?42 and phosphorylated tau (P-tau) that were seen in several regions, novel CSF proteins were found to have effects in inferior and middle temporal cortex (including apolipoprotein CIII, apolipoprotein D, and apolipoprotein H). Several proteins (including S100? and matrix metalloproteinase-3) had effects that depended on the presence of brain A? pathology, as measured by CSF A?42. Other proteins (including P-tau and apolipoprotein D) had effects even after adjusting for CSF A?42. The statistical effects in this exploratory study were mild and not significant after correction for multiple comparisons, but some of the identified proteins may be associated with brain atrophy in healthy persons. Proteins interacting with CSF A?42 may be related to A? brain pathology, whereas proteins associated with atrophy even after adjusting for CSF A?42 may be related to A?-independent mechanisms.
| S-EPMC3864623 | biostudies-literature
Project description:Females live longer than males, and there are sex disparities in physical health and disease incidence. However, sex differences in biological aging have not been consistently reported and may differ depending on the measure used. This study aimed to determine the correlations between epigenetic age acceleration (AA), and other markers of biological aging, separately in males and females. We additionally explored the extent to which these AA measures differed according to socioeconomic characteristics, clinical markers, and diseases. Epigenetic clocks (HorvathAge, HannumAge, PhenoAge, GrimAge, GrimAge2, and DunedinPACE) were estimated in blood from 560 relatively healthy Australians aged ≥ 70 years (females, 50.7%) enrolled in the ASPREE study. A system-wide deficit accumulation frailty index (FI) composed of 67 health-related measures was generated. Brain age and subsequently brain-predicted age difference (brain-PAD) were estimated from neuroimaging. Females had significantly reduced AA than males, but higher FI, and there was no difference in brain-PAD. FI had the strongest correlation with DunedinPACE (range r: 0.21 to 0.24 in both sexes). Brain-PAD was not correlated with any biological aging measures. Significant correlations between AA and sociodemographic characteristics and health markers were more commonly found in females (e.g., for DunedinPACE and systolic blood pressure r = 0.2, p < 0.001) than in males. GrimAA and Grim2AA were significantly associated with obesity and depression in females, while in males, hypertension, diabetes, and chronic kidney disease were associated with these clocks, as well as DunedinPACE. Our findings highlight the importance of considering sex differences when investigating the link between biological age and clinical measures.
| S-EPMC10828143 | biostudies-literature
Project description:Episodic memory decline is an early symptom of Alzheimer's disease (AD) - a neurodegenerative disease that has a higher prevalence rate in older females compared to older males. However, little is known about why these sex differences in prevalence rate exist. In the current longitudinal task fMRI study, we explored whether there were sex differences in the patterns of memory decline and brain activity during object-location (spatial context) encoding and retrieval in a large sample of cognitively unimpaired older adults from the Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer's Disease (PREVENT-AD) program who are at heightened risk of developing AD due to having a family history (+FH) of the disease. The goal of the study was to gain insight into whether there are sex differences in the neural correlates of episodic memory decline, which may advance knowledge about sex-specific patterns in the natural progression to AD. Our results indicate that +FH females performed better than +FH males at both baseline and follow-up on neuropsychological and task fMRI measures of episodic memory. Moreover, multivariate data-driven task fMRI analysis identified generalized patterns of longitudinal decline in medial temporal lobe activity that was paralleled by longitudinal increases in lateral prefrontal cortex, caudate and midline cortical activity during successful episodic retrieval and novelty detection in +FH males, but not females. Post-hoc analyses indicated that higher education had a stronger effect on +FH females neuropsychological scores compared to +FH males. We conclude that higher educational attainment may have a greater neuroprotective effect in older +FH females compared to +FH males.
| S-EPMC10652211 | biostudies-literature
Project description:Age and sex can influence brain iron levels. We studied the influence of these variables on deep gray matter magnetic susceptibilities. In 183 healthy volunteers (44.7 ± 14.2 years, range 20-69, ? 49%), in vivo quantitative susceptibility mapping (QSM) at 1.5T was performed to estimate brain iron accumulation in the following regions of interest (ROIs): caudate nucleus (Cd), putamen (Pt), globus pallidus (Gp), thalamus (Th), pulvinar (Pul), red nucleus (Rn), substantia nigra (Sn) and the cerebellar dentate nuclei (Dn). We gauged the influence of age and sex on magnetic susceptibility by specifying a series of structural equation models. The distributions of susceptibility varied in degree across the structures, conforming to histologic findings (Hallgren and Sourander, 1958), with the highest degree of susceptibility in the Gp and the lowest in the Th. Iron increase correlated across several ROIs, which may reflect an underlying age-related process. Advanced age was associated with a particularly strong linear rise of susceptibility in the striatum. Nonlinear age trends were found in the Rn, where they were the most pronounced, followed by the Pul and Sn, while minimal nonlinear trends were observed for the Pt, Th, and Dn. Moreover, sex related variations were observed, so that women showed lower levels of susceptibility in the Sn after accounting for age. Regional susceptibility of the Pul increased linearly with age in men but exhibited a nonlinear association with age in women with a leveling off starting from midlife. Women expected to be post menopause (+51 years) showed lower total magnetic susceptibility in the subcortical gray matter. The current report not only is consistent with previous reports of age related variations of brain iron, but also adds to the current knowledge by reporting age-related changes in less studied, smaller subcortical nuclei. This is the first in-vivo report to show lower total subcortical brain iron levels selectively in women from midlife, compared to men and younger women. These results encourage further assessment of sex differences in brain iron. We anticipate that age and sex are important co-factors to take into account when establishing a baseline level for differentiating pathologic neurodegeneration from healthy aging. The variations in regional susceptibility reported herein should be evaluated further using a longitudinal study design to determine within-person changes in aging.
| S-EPMC4737643 | biostudies-literature
Project description:APOE-ε4 is a main genetic risk factor for developing late onset Alzheimer's disease (LOAD) and is thought to interact adversely with other risk factors on the brain. However, evidence regarding the impact of APOE-ε4 on grey matter structure in asymptomatic individuals remains mixed. Much attention has been devoted to characterising APOE-ε4-related changes in the hippocampus, but LOAD pathology is known to spread through the whole of the Papez circuit including the limbic thalamus. Here, we tested the impact of APOE-ε4 and two other risk factors, a family history of dementia and obesity, on grey matter macro- and microstructure across the whole brain in 165 asymptomatic individuals (38-71 years). Microstructural properties of apparent neurite density and dispersion, free water, myelin and cell metabolism were assessed with Neurite Orientation Density and Dispersion (NODDI) and quantitative magnetization transfer (qMT) imaging. APOE-ε4 carriers relative to non-carriers had a lower macromolecular proton fraction (MPF) in the left thalamus. No risk effects were present for cortical thickness, subcortical volume, or NODDI indices. Reduced thalamic MPF may reflect inflammation-related tissue swelling and/or myelin loss in APOE-ε4. Future prospective studies should investigate the sensitivity and specificity of qMT-based MPF as a non-invasive biomarker for LOAD risk.
| S-EPMC7666117 | biostudies-literature
Project description:Excessive daytime sleepiness (EDS) and fatigue increases with age. The aim of this study was to investigate the association between EDS and fatigue with cortical thickness and hippocampal volume in cognitively normal, late middle-aged and older adults. We performed a cross-sectional observational study of 1374 cognitively-normal subjects aged 50 years and older who had a structural MRI. Regional cortical thickness and hippocampal volume were measured. Multiple linear regression models were fit to explore associations between EDS and fatigue and structural MRI measures in different brain regions, adjusting for multiple covariates. EDS was defined as Epworth Sleepiness Scale ?10. Fatigue severity was assessed with the Beck Depression Inventory-2. 208 participants had EDS, 27 had significant fatigue, and 11 had both. Participants with EDS or fatigue had significantly lower cognitive scores, more disturbed sleep, and medical comorbidities. The presence of EDS was associated with both global and regional atrophy, whereas fatigue was more associated with frontal and temporal changes. Cortical thinning predicted by EDS and fatigue was maximal in the temporal region with average reduction of 34.2 ?m (95% CI, -54.1, -14.3; P = 0.001) and 90.2 ?m (95% CI, -142.1, -38.2; P = 0.001), respectively. Fatigue was also associated with hippocampal volume reduction of -374.2 mm3 (95% CI, -670.8, -77.7; P = 0.013). Temporal cortical thinning predicted by presence of EDS and fatigue was equivalent to more than 3.5 and 9 additional years of aging, respectively. EDS and fatigue were associated with cortical thickness reduction primarily in regions with increased age-susceptibility, which may indicate accelerated brain aging.
| S-EPMC5551490 | biostudies-literature
Project description:The biological basis for gender variability among disease states is not well established. There have been many prior efforts attempting to identify the unique urine metabolomic profiles associated with specific diseases. However, there has been little advancement in investigating the metabolomic differences associated with gender, which underlies the misconception that risk factors and treatment regimens should be the same for both male and female patients. This present study aimed to identify biologically-meaningful baseline sex-related differences using urine samples provided by healthy female and male participants. To elucidate whether urinary metabolic signatures are globally distinct between healthy males and females, we applied metabolomics profiling of primary metabolism with comprehensive bioinformatics analyses on urine samples from 60 healthy males and females. We found that levels of ?-ketoglutarate and 4-hydroxybutyric acid increased 2.3-fold and 4.41-fold in males compared to females, respectively. Furthermore, chemical similarity enrichment analysis revealed that differentially expressed metabolites, such as saturated fatty acids, TCA, and butyrates, were significantly related to the gender effect. These findings indicate that there are baseline sex-related differences in urinary metabolism, which should be considered in biomarker discovery, diagnosis, and treatment of bladder diseases, such as interstitial cystitis.
| S-EPMC6082868 | biostudies-other