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 (??=?-0.036, SE?=?0.011, p?=?0.001) and erc (??=?-0.019, SE?=?0.009, p?=?0.045). Sex modified the association of PiB+ status and rates of volumetric declines in fusiform (??=?-0.117, SE?=?0.049, p?=?0.019). PiB+ males had steeper rates of volumetric declines in phg (??=?-0.051, SE?=?0.013, p?<?0.001) and erc (??=?-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: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-?4 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-?4 on grey matter structure in asymptomatic individuals remains mixed. Much attention has been devoted to characterising APOE-?4-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-?4 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-?4 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-?4. 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:BackgroundAge-related brain changes leading to altered socioemotional functioning may increase vulnerability to financial exploitation. If confirmed, this would suggest a novel mechanism leading to heightened financial exploitation risk in older adults. Development of predictive neural markers could facilitate increased vigilance and prevention. In this preliminary study, we sought to identify structural and functional brain differences associated with financial exploitation in older adults.MethodsFinancially exploited older adults (n = 13, 7 female) and a matched cohort of older adults who had been exposed to, but avoided, a potentially exploitative situation (n = 13, 7 female) were evaluated. Using magnetic resonance imaging, we examined cortical thickness and resting state functional connectivity. Behavioral data were collected using standardized cognitive assessments, self-report measures of mood and social functioning.ResultsThe exploited group showed cortical thinning in anterior insula and posterior superior temporal cortices, regions associated with processing affective and social information, respectively. Functional connectivity encompassing these regions, within default and salience networks, was reduced, while between network connectivity was increased. Self-reported anger and hostility was higher for the exploited group.ConclusionsWe observed financial exploitation associated with brain differences in regions involved in socioemotional functioning. These exploratory and preliminary findings suggest that alterations in brain regions implicated in socioemotional functioning may be a marker of financial exploitation risk. Large-scale, prospective studies are necessary to validate this neural mechanism, and develop predictive markers for use in clinical practice.
| S-EPMC5861949 | biostudies-literature
Project description:Compensation implies the recruitment of additional neuronal resources to prevent the detrimental effect of age-related neuronal decline on cognition. Recently suggested statistical models comprise behavioral performance, brain activation, and measures related to aging- or disease-specific pathological burden to characterize compensation. Higher chronological age as well as the APOE ?4 allele are risk factors for Alzheimer's disease. A more biological approach to characterize aging compared with chronological age is the brain age gap estimation (BrainAGE), taking into account structural brain characteristics. We utilized this estimate in an fMRI experiment together with APOE variant as measures related to pathological burden and aimed at identifying compensatory regions during working memory (WM) processing in a group of 34 healthy older adults. According to published compensation criteria, better performance along with increased brain activation would indicate successful compensation. We examined the moderating effects of BrainAGE on the relationship between task performance and brain activation in prefrontal cortex, as previous studies suggest predominantly frontal compensatory activation. Then we statistically compared them to the effects of chronological age (CA) tested in a previous study. Moreover, we examined the effects of adding APOE variant as a further moderator. Herewith, we strived to uncover neuronal compensation in healthy older adults at risk for neurodegenerative disease. Higher BrainAGE alone was not associated with an increased recruitment in prefrontal cortex. When adding APOE variant as a second moderator, we found an interaction of BrainAGE and APOE variant, such that ?4 carriers recruited right inferior frontal gyrus with higher BrainAGE to maintain WM performance, thus showing a pattern compatible with successful neuronal compensation. Exploratory analyses yielded similar patterns in left inferior and bilateral middle frontal gyrus. These results contrast those from a previous study, where we found no indication of compensation in prefrontal cortex in ?4 carriers with increasing CA. We conclude that BrainAGE together with APOE variant can help to reveal potential neuronal compensation in healthy older adults. Previous results on neuronal compensation in frontal areas corroborate our findings. Compensatory brain regions could be targeted in affected individuals by training or stimulation protocols to maintain cognitive functioning as long as possible.
| S-EPMC5869204 | 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