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ObjectivesChildhood disadvantage is associated with lower general cognitive ability (GCA) and brain structural differences in midlife and older adulthood. However, the neuroanatomical mechanisms underlying childhood disadvantage effects on later-life GCA remain poorly understood. Although total surface area (SA) has been linked to lifespan GCA differences, total SA does not capture the nonuniform nature of childhood disadvantage effects on neuroanatomy, which varies across unimodal and transmodal cortices. Here, we examined whether cortical SA profile-the extent to which the spatial patterning of SA deviates from the normative unimodal-transmodal cortical organization-is a mediator of childhood disadvantage effects on later-life GCA.MethodsIn 477 community-dwelling men aged 56-72 years old, childhood disadvantage index was derived from four indicators of disadvantages and GCA was assessed using a standardized test. Cortical SA was obtained from structural magnetic resonance imaging. For cortical SA profile, we calculated the spatial similarity between maps of individual cortical SA and MRI-derived principal gradient (i.e., unimodal-transmodal organization). Mediation analyses were conducted to examine the indirect effects of childhood disadvantage index through cortical SA profile on GCA.ResultsAround 1.31% of childhood disadvantage index effects on later-life GCA were mediated by cortical SA profile, whereas total SA did not. Higher childhood disadvantage index was associated with more deviation of the cortical SA spatial patterning from the principal gradient, which in turn related to lower later-life GCA.DiscussionChildhood disadvantage may contribute to later-life GCA differences partly by influencing the spatial patterning of cortical SA in a way that deviates from the normative cortical organizational principle.

Abstract: Background: Early identification of Alzheimer’s disease (AD) risk prior to irreversible brain damage is critical for improving the success of interventions and treatment. Cortical thickness is a macrostructural measure typically used to assess AD neurodegeneration. However, cortical microstructural changes appear to precede macrostructural atrophy and may improve early identification of AD risk. Currently, whether cortical microstructural neurodegeneration in aging is linked to early vulnerability to AD pathophysiology remains unclear in non‐clinical populations, who are precisely the target population for early risk identification. Method: In 194 dementia‐free community‐dwelling adults, we calculated MRI‐derived group‐level brain maps of longitudinal changes in cortical mean diffusivity (microstructure) and cortical thickness (macrostructure) over 5‐6 years (mean age: Time 1=61.82; Time 2=67.48). We obtained PET‐derived group‐level brain maps of stereotypical AD pathology deposition (beta‐amyloid and tau) and density maps of neurotransmitter receptors (cholinergic, glutamatergic) implicated in AD pathophysiology. An MRI‐derived map of cortical organization (sensorimotor‐association axis) was used to probe general age‐related changes. Spatial correlational analyses were used to compare pattern similarity among maps. We first examined whether changes in cortical microstructure and macrostructure are enriched in regions with increased accumulation of beta‐amyloid and tau, and higher density of cholinergic and glutamatergic receptors. We then investigated whether individuals with more AD‐like change profiles (spatially similar to beta‐amyloid or tau deposition patterns) showed greater memory decline as measured by three well‐established neuropsychological tests. Result: Spatial patterns of cortical macrostructural changes only resembled patterns of cortical organization sensitive to general age‐related processes (r=‐0.31, p

ObjectiveIdentifying persons with HIV (PWH) at increased risk for Alzheimer's disease (AD) is complicated because memory deficits are common in HIV-associated neurocognitive disorders (HAND) and a defining feature of amnestic mild cognitive impairment (aMCI; a precursor to AD). Recognition memory deficits may be useful in differentiating these etiologies. Therefore, neuroimaging correlates of different memory deficits (i.e., recall, recognition) and their longitudinal trajectories in PWH were examined.DesignWe examined 92 PWH from the CHARTER Program, ages 45-68, without severe comorbid conditions, who received baseline structural MRI and baseline and longitudinal neuropsychological testing. Linear and logistic regression examined neuroanatomical correlates (i.e., cortical thickness and volumes of regions associated with HAND and/or AD) of memory performance at baseline and multilevel modeling examined neuroanatomical correlates of memory decline (average follow-up = 6.5 years).ResultsAt baseline, thinner pars opercularis cortex was associated with impaired recognition (p = 0.012; p = 0.060 after correcting for multiple comparisons). Worse delayed recall was associated with thinner pars opercularis (p = 0.001) and thinner rostral middle frontal cortex (p = 0.006) cross sectionally even after correcting for multiple comparisons. Delayed recall and recognition were not associated with medial temporal lobe (MTL), basal ganglia, or other prefrontal structures. Recognition impairment was variable over time, and there was little decline in delayed recall. Baseline MTL and prefrontal structures were not associated with delayed recall.ConclusionsEpisodic memory was associated with prefrontal structures, and MTL and prefrontal structures did not predict memory decline. There was relative stability in memory over time. Findings suggest that episodic memory is more related to frontal structures, rather than encroaching AD pathology, in middle-aged PWH. Additional research should clarify if recognition is useful clinically to differentiate aMCI and HAND.

Eating disorders (EDs) are multifaceted psychiatric disorders characterized by varying behaviors, traits, and cognitive profiles thought to drive symptom heterogeneity and severity. Non-invasive neuroimaging methods have been critical to elucidate the neurobiological circuitry involved in ED-related behaviors, but often focused on a limited set of regions of interest and/or symptoms. The current study harnesses multivariate methods to map microstructural and morphometric patterns across the entire brain to multiple domains of behavior and symptomatology in patients. Diffusion-weighted images, modeled with restriction spectrum imaging, were analyzed for 91 adolescent patients with an ED and 48 healthy controls. Partial least squares analysis was applied to map 38 behavioral measures (encompassing cognition, temperament, and ED symptoms) to restricted diffusion in white matter tracts and subcortical structures across 65 regions of interest. The first significant latent variable explained 46.9% of the covariance between microstructure and behavior. This latent variable retained a significant brain-behavior correlation in held-out data, where an 'undercontrolled' behavioral profile (e.g., higher emotional dysregulation, novelty seeking; lower effortful control and interoceptive awareness) was linked to increased restricted diffusion across white matter tracts, particularly those joining frontal, limbic, and thalamic regions. Individually-derived brain and behavior scores for this latent variable were higher in patients with binge-purge symptoms, compared to those with only restrictive eating symptoms. Findings demonstrate the value of applying multivariate modeling to the array of brain-behavior relationships inherent to the clinical presentation of EDs, and their relevance for providing a neurobiologically-informed model for future clinical subtyping and prediction efforts.

BackgroundChronic pain leads to tau accumulation and hippocampal atrophy, which may be moderated through inflammation. In older men, we examined associations of chronic pain with Alzheimer's disease (AD)-related plasma biomarkers and hippocampal volume as moderated by systemic inflammation.MethodsParticipants were men without dementia. Chronic pain was defined as moderate-to-severe pain in 2+ study waves at average ages 56, 62, and 68. At age 68, we measured plasma amyloid-beta (Aβ42, n = 871), Aβ40 (n = 887), total tau (t-tau, n = 841), and neurofilament light chain (NfL, n = 915), and serum high-sensitivity C-reactive protein (hs-CRP, n = 968), a marker of systemic inflammation. A subgroup underwent structural MRI to measure hippocampal volume (n = 385). Analyses adjusted for medical morbidities, depressive symptoms, and opioid use.ResultsChronic pain was related to higher Aβ40 (β = 0.25, p = .009), but hs-CRP was unrelated to AD-related biomarkers (ps > .05). There was a significant interaction such that older men with both chronic pain and higher levels of hs-CRP had higher levels of Aβ42 (β = 0.36, p = .001) and Aβ40 (β = 0.29, p = .003). Chronic pain and hs-CRP did not interact to predict levels of Aβ42/Aβ40, t-tau, or NfL. Furthermore, there were significant interactions such that Aβ42 and Aβ40 were associated with lower hippocampal volume, particularly when levels of hs-CRP were elevated (hs-CRP × Aβ42: β = -0.19, p = .002; hs-CRP × Aβ40: β = -0.21, p = .001), regardless of chronic pain status.ConclusionsChronic pain was associated with higher plasma Aβ, especially when hs-CRP was also elevated. Higher hs-CRP and Aβ levels were both related to smaller hippocampal volumes. Chronic pain, when accompanied by systemic inflammation, may elevate the risk of neurodegeneration in AD-vulnerable regions.

BackgroundEarly identification of Alzheimer's disease (AD) risk is critical for improving treatment success. Cortical thickness is a macrostructural measure used to assess neurodegeneration in AD. However, cortical microstructural changes appear to precede macrostructural atrophy and may improve early risk identification. Currently, whether cortical microstructural changes in aging are linked to vulnerability to AD pathophysiology remains unclear in nonclinical populations, who are precisely the target for early risk identification.MethodsIn 194 adults, we calculated magnetic resonance imaging-derived maps of changes in cortical mean diffusivity (microstructure) and cortical thickness (macrostructure) over 5 to 6 years (mean age: time 1 = 61.82 years; time 2 = 67.48 years). Episodic memory was assessed using 3 well-established tests. We obtained positron emission tomography-derived maps of AD pathology deposition (amyloid-β, tau) and neurotransmitter receptors (cholinergic, glutamatergic) implicated in AD pathophysiology. Spatial correlational analyses were used to compare pattern similarity among maps.ResultsSpatial patterns of cortical macrostructural changes resembled patterns of cortical organization sensitive to age-related processes (r = -0.31, p < .05), whereas microstructural changes resembled the patterns of tau deposition in AD (r = 0.39, p = .038). Individuals with patterns of microstructural changes that more closely resembled stereotypical tau deposition exhibited greater memory decline (β = 0.22, p = .029). Microstructural changes and AD pathology deposition were enriched in areas with greater densities of cholinergic and glutamatergic receptors (ps < .05).ConclusionsPatterns of cortical microstructural changes were more AD-like than patterns of macrostructural changes, which appeared to reflect more general aging processes. Microstructural changes may better inform early risk prediction efforts as a sensitive measure of vulnerability to pathological processes prior to overt atrophy and cognitive decline.

BackgroundChildhood disadvantage is a prominent risk factor for cognitive and brain aging. Childhood disadvantage is associated with poorer episodic memory in late midlife and functional and structural brain abnormalities in the default mode network (DMN). Although age-related changes in DMN are associated with episodic memory declines in older adults, it remains unclear if childhood disadvantage has an enduring impact on this later-life brain-cognition relationship earlier in the aging process. Here, within the DMN, we examined whether its cortical microstructural integrity-an early marker of structural vulnerability that increases the risk for future cognitive decline and neurodegeneration-is associated with episodic memory in adults at ages 56-66, and whether childhood disadvantage moderates this association.MethodsCortical mean diffusivity (MD) obtained from diffusion magnetic resonance imaging was used to measure microstructural integrity in 350 community-dwelling men. We examined both visual and verbal episodic memory in relation to DMN MD and divided participants into disadvantaged and nondisadvantaged groups based on parental education and occupation.ResultsHigher DMN MD was associated with poorer visual memory but not verbal memory (β = -0.11, p = .040 vs β = -0.04, p = .535). This association was moderated by childhood disadvantage and was significant only in the disadvantaged group (β = -0.26, p = .002 vs β = -0.00, p = .957).ConclusionsLower DMN cortical microstructural integrity may reflect visual memory vulnerability in cognitively normal adults earlier in the aging process. Individuals who experienced childhood disadvantage manifested greater vulnerability to cortical microstructure-related visual memory dysfunction than their nondisadvantaged counterparts who exhibited resilience in the face of low cortical microstructural integrity.

BackgroundPlasma neurofilament light chain (NfL) is a promising biomarker of neurodegeneration with potential clinical utility in monitoring the progression of neurodegenerative diseases. However, the cross-sectional associations of plasma NfL with measures of cognition and brain have been inconsistent in community-dwelling populations.MethodsWe examined these associations in a large community-dwelling sample of early old age men (N = 969, mean age = 67.57 years, range = 61-73 years), who are either cognitively unimpaired (CU) or with mild cognitive impairment (MCI). Specifically, we investigated five cognitive domains (executive function, episodic memory, verbal fluency, processing speed, visual-spatial ability), as well as neuroimaging measures of gray and white matter.ResultsAfter adjusting for age, health status, and young adult general cognitive ability, plasma NfL level was only significantly associated with processing speed and white matter hyperintensity (WMH) volume, but not with other cognitive or neuroimaging measures. The association with processing speed was driven by individuals with MCI, as it was not detected in CU individuals.ConclusionsThese results suggest that in early old age men without dementia, plasma NfL does not appear to be sensitive to cross-sectional individual differences in most domains of cognition or neuroimaging measures of gray and white matter. The revealed plasma NfL associations were limited to WMH for all participants and processing speed only within the MCI cohort. Importantly, considering cognitive status in community-based samples will better inform the interpretation of the relationships of plasma NfL with cognition and brain and may help resolve mixed findings in the literature.

Introduction Neuropathological studies indicate that abnormal tau may first appear in the locus coeruleus (LC) starting early in life, (1,2) with substantial accumulation occurring during the course of Alzheimer's disease [...], BACKGROUND: Increased exposure to ambient air pollution, especially fine particulate matter [less than or equal to]2.5 [micro]m ([PM.sub.2.5]) is associated with poorer brain health and increased risk for Alzheimer&apos;s disease (AD) and related dementias. The locus coeruleus (LC), located in the brainstem, is one of the earliest regions affected by tau pathology seen in AD. Its diffuse projections throughout the brain include afferents to olfactory areas that are hypothesized conduits of cerebral particle deposition. Additionally, extensive contact of the LC with the cerebrovascular system may present an additional route of exposure to environmental toxicants. OBJECTIVE: Our aim was to investigate if exposure to [PM.sub.2.5] was associated with LC integrity in a nationwide sample of men in early old age, potentially representing one pathway through which air pollution can contribute to increased risk for AD dementia. METHODS: We examined the relationship between [PM.sub.2.5] and in vivo magnetic resonance imaging (MRI) estimates of LC structural integrity indexed by contrast to noise ratio ([LC.sub.CNR]) in 381 men [mean age = 67.3; standard deviation (SD) = 2.6] from the Vietnam Era Twin Study of Aging (VETSA). Exposure to [PM.sub.2.5] was taken as a 3-year average over the most recent period for which data were available (average of 5.6 years prior to the MRI scan). We focused on [LC.sub.CNR] in the rostral-middle portion of LC due to its stronger associations with aging and AD than the caudal LC. Associations between [PM.sub.2.5] exposures and LC integrity were tested using linear mixed effects models adjusted for age, scanner, education, household income, and interval between exposure and MRI. A co-twin control analysis was also performed to investigate whether associations remained after controlling for genetic confounding and rearing environment. RESULTS: Multiple linear regressions revealed a significant association between [PM.sub.2.5] and rostral-middle [LC.sub.CNR] (b = -0.16; p = 0.02), whereby higher exposure to [PM.sub.2.5] was associated with lower [LC.sub.CNR]. A co-twin control analysis found that, within monozygotic pairs, individuals with higher [PM.sub.2.5] exposure showed lower [LC.sub.CNR] (b = - 0.11; p = 0.02), indicating associations were not driven by genetic or shared environmental confounds. There were no associations between [PM.sub.2.5] and caudal [LC.sub.CNR] or hippocampal volume, suggesting a degree of specificity to the rostral-middle portion of the LC. DISCUSSION: Given previous findings that loss of LC integrity is associated with increased accumulation of AD-related amyloid and tau pathology, impacts on LC integrity may represent a potential pathway through which exposure to air pollution increases AD risk. https://doi.org/10.1289/EHP14344

ObjectivesAbnormal tau, a hallmark Alzheimer's disease (AD) pathology, may appear in the locus coeruleus (LC) decades before AD symptom onset. Reports of subjective cognitive decline are also often present prior to formal diagnosis. Yet, the relationship between LC structural integrity and subjective cognitive decline has remained unexplored. Here, we aimed to explore these potential associations.MethodsWe examined 381 community-dwelling men (mean age = 67.58; SD = 2.62) in the Vietnam Era Twin Study of Aging who underwent LC-sensitive magnetic resonance imaging and completed the Everyday Cognition scale to measure subjective cognitive decline along with their selected informants. Mixed models examined the associations between rostral-middle and caudal LC integrity and subjective cognitive decline after adjusting for depressive symptoms, physical morbidities, and family. Models also adjusted for current objective cognitive performance and objective cognitive decline to explore attenuation.ResultsFor participant ratings, lower rostral-middle LC contrast to noise ratio (LCCNR) was associated with significantly greater subjective decline in memory, executive function, and visuospatial abilities. For informant ratings, lower rostral-middle LCCNR was associated with significantly greater subjective decline in memory only. Associations remained after adjusting for current objective cognition and objective cognitive decline in respective domains.ConclusionsLower rostral-middle LC integrity is associated with greater subjective cognitive decline. Although not explained by objective cognitive performance, such a relationship may explain increased AD risk in people with subjective cognitive decline as the LC is an important neural substrate important for higher order cognitive processing, attention, and arousal and one of the first sites of AD pathology.

Some evidence suggests a biphasic pattern of changes in cortical thickness wherein higher, rather than lower, thickness is associated with very early Alzheimer's disease (AD) pathology. We examined whether integrating information from AD brain signatures based on mean diffusivity (MD) can aid in the interpretation of cortical thickness/volume as a risk factor for future AD-related changes. Participants were 572 men in the Vietnam Era Twin Study of Aging who were cognitively unimpaired at baseline (mean age = 56 years; range = 51-60). Individuals with both high thickness/volume signatures and high MD signatures at baseline had lower cortical thickness/volume in AD signature regions and lower episodic memory performance 12 years later compared to those with high thickness/volume and low MD signatures at baseline. Groups did not differ in level of young adult cognitive reserve. Our findings are in line with a biphasic model in which increased cortical thickness may precede future decline and establish the value of examining cortical MD alongside cortical thickness to identify subgroups with differential risk for poorer brain and cognitive outcomes.

BackgroundComposite scores of magnetic resonance imaging-derived metrics in brain regions associated with Alzheimer's disease (AD), commonly termed AD signatures, have been developed to distinguish early AD-related atrophy from normal age-associated changes. Diffusion-based gray matter signatures may be more sensitive to early AD-related changes compared with thickness/volume-based signatures, demonstrating their potential clinical utility. The timing of early (i.e., midlife) changes in AD signatures from different modalities and whether diffusion- and thickness/volume-based signatures each capture unique AD-related phenotypic or genetic information remains unknown.MethodsOur validated thickness/volume signature, our novel mean diffusivity (MD) signature, and a magnetic resonance imaging-derived measure of brain age were used in biometrical analyses to examine genetic and environmental influences on the measures as well as phenotypic and genetic relationships between measures over 12 years. Participants were 736 men from 3 waves of the Vietnam Era Twin Study of Aging (VETSA) (baseline/wave 1: mean age [years] = 56.1, SD = 2.6, range = 51.1-60.2). Subsequent waves occurred at approximately 5.7-year intervals.ResultsMD and thickness/volume signatures were highly heritable (56%-72%). Baseline MD signatures predicted thickness/volume signatures over a decade later, but baseline thickness/volume signatures showed a significantly weaker relationship with future MD signatures. AD signatures and brain age were correlated, but each measure captured unique phenotypic and genetic variance.ConclusionsCortical MD and thickness/volume AD signatures are heritable, and each signature captures unique variance that is also not explained by brain age. Moreover, results are in line with changes in MD emerging before changes in cortical thickness, underscoring the utility of MD as a very early predictor of AD risk.

Executive function encompasses effortful cognitive processes that are particularly susceptible to aging. Functional brain networks supporting executive function-such as the frontoparietal control network and the multiple demand system-have been extensively investigated. However, it remains unclear how structural networks facilitate and constrain the dynamics of functional networks to contribute to aging-related executive function declines. We examined whether changes in structural network modal controllability-a network's ability to facilitate effortful brain state transitions that support cognitive functions-are associated with changes in executive function cross-sectionally and longitudinally. Diffusion-weighted imaging and neuropsychological testing were conducted at two time points (Time 1: ages 56 to 66, N = 172; Time 2: ages 61 to 70, N = 267) in community-dwelling men from the Vietnam Era Twin Study of Aging. An executive function factor score was computed from six neuropsychological tasks. Structural networks constructed from white matter connectivity were used to estimate modal controllability in control network and multiple demand system. We showed that higher modal controllability in control network and multiple demand system was associated with better executive function at Time 2, after controlling for age, young adult general cognitive ability, and physical health status. Moreover, changes in executive function over a period of 5 to 6 years (Time 1-Time 2, N = 105) were associated with changes in modal controllability of the multiple demand system and weakly in the control network over the same time period. These findings suggest that changes in the ability of structural brain networks in facilitating effortful brain state transitions may be a key neural mechanism underlying aging-related executive function declines and cognitive aging.

BackgroundFine particulate matter (PM2.5) and nitrogen dioxide (NO2) measures of ambient air pollution are associated with accelerated age-related cognitive impairment, and Alzheimer's disease and related dementias (ADRD).ObjectiveWe examined associations between air pollution, four cognitive factors, and the moderating role of apolipoprotein E (APOE) genotype in the understudied period of midlife.MethodsParticipants were ∼1,100 men in the Vietnam Era Twin Study of Aging. Baseline cognitive assessments were from 2003 to 2007. Measures included past (1993-1999) and recent (3 years prior to baseline assessment) PM2.5 and NO2 exposure, in-person assessment of episodic memory, executive function, verbal fluency, and processing speed, and APOE genotype. Average baseline age was 56 years with a 12-year follow-up. Analyses adjusted for health and lifestyle covariates.ResultsPerformance in all cognitive domains declined from age 56 to 68. Higher PM2.5 exposures were associated with worse general verbal fluency. We found significant exposure-by-APOE genotype interactions for specific cognitive domains: PM2.5 with executive function and NO2 with episodic memory. Higher PM2.5 exposure was related to worse executive function in APOE ɛ4 carriers, but not in non-carriers. There were no associations with processing speed.ConclusionThese results indicate negative effects of ambient air pollution exposure on fluency alongside intriguing differential modifications of cognitive performance by APOE genotype. APOE ɛ4 carriers appeared more sensitive to environmental differences. The process by which air pollution and its interaction with genetic risk for ADRD affects risk for later life cognitive decline or progression to dementia may begin in midlife.

Structural brain abnormalities, including those in white matter (WM), remain common in people with HIV (PWH). Their pathogenesis is uncertain and may reflect multiple etiologies. Oxidative stress is associated with inflammation, HIV, and its comorbidities. The post-translational carbonylation of proteins results from oxidative stress, and circulating protein carbonyls may reflect this. In this cross-sectional analysis, we evaluated the associations between protein carbonyls and a panel of soluble biomarkers of neuronal injury and inflammation in plasma (N = 45) and cerebrospinal fluid (CSF, n = 32) with structural brain MRI. The volume of abnormal WM was normalized for the total WM volume (nAWM). In this multisite project, all regression models were adjusted for the scanner. The candidate covariates included demographics, HIV disease characteristics, and comorbidities. Participants were PWH on virally suppressive antiretroviral therapy (ART) and were mostly white (64.4%) men (88.9%), with a mean age of 56.8 years. In unadjusted analyses, more nAWM was associated with higher plasma protein carbonyls (p = 0.002) and higher CCL2 (p = 0.045). In the adjusted regression models for nAWM, the association with plasma protein carbonyls remained significant (FDR p = 0.018). Protein carbonyls in plasma may be a valuable biomarker of oxidative stress and its associated adverse health effects, including within the central nervous system. If confirmed, these findings would support the hypothesis that reducing oxidative stress could treat or prevent WM injury in PWH.

BackgroundStudies have investigated white matter microstructure in relation to late-life cognitive impairments, with fractional anisotropy (FA) and mean diffusivity (MD) measures thought to capture demyelination and axonal degradation. However, new post-processing methods allow isolation of free water (FW), which captures extracellular fluid contributions such as atrophy and neuroinflammation, from tissue components. FW also appears to be highly relevant to late-life cognitive impairment. Here, we evaluated whether executive functions are associated with FW, and FA and MD corrected for FW (FAFWcorr and MDFWcorr).MethodWe examined 489 non-demented men in the Vietnam Era Twin Study of Aging (VETSA) at mean age 68. Two latent factors capturing 'common executive function' and 'working-memory specific' processes were estimated based on 6 tasks. Analyses focused on 11 cortical white matter tracts across three metrics: FW, FAFWcorr, and MDFWcorr.ResultsBetter 'common executive function' was associated with lower FW across 9 of the 11 tracts. There were no significant associations with intracellular metrics after false discovery rate correction. Effects also appeared driven by individuals with MCI (13.7% of the sample). Working memory-specific tasks showed some associations with FAFWcorr, including the triangularis portion of the inferior frontal gyrus. There was no evidence that cognitive reserve (i.e., general cognitive ability assessed in early adulthood) moderated these associations between executive function and FW or FA.DiscussionExecutive function abilities in early old age are associated primarily with extracellular fluid (FW) as opposed to white matter (FAFWcorr or MDFWcorr). Moderation analyses suggested cognitive reserve does not play a strong role in these associations, at least in this sample of non-demented men.

BackgroundClarifying the relationship between depression symptoms and cardiometabolic and related health could clarify risk factors and treatment targets. The objective of this study was to assess whether depression symptoms in midlife are associated with the subsequent onset of cardiometabolic health problems.MethodsThe study sample comprised 787 male twin veterans with polygenic risk score data who participated in the Harvard Twin Study of Substance Abuse ('baseline') and the longitudinal Vietnam Era Twin Study of Aging ('follow-up'). Depression symptoms were assessed at baseline [mean age 41.42 years (s.d. = 2.34)] using the Diagnostic Interview Schedule, Version III, Revised. The onset of eight cardiometabolic conditions (atrial fibrillation, diabetes, erectile dysfunction, hypercholesterolemia, hypertension, myocardial infarction, sleep apnea, and stroke) was assessed via self-reported doctor diagnosis at follow-up [mean age 67.59 years (s.d. = 2.41)].ResultsTotal depression symptoms were longitudinally associated with incident diabetes (OR 1.29, 95% CI 1.07-1.57), erectile dysfunction (OR 1.32, 95% CI 1.10-1.59), hypercholesterolemia (OR 1.26, 95% CI 1.04-1.53), and sleep apnea (OR 1.40, 95% CI 1.13-1.74) over 27 years after controlling for age, alcohol consumption, smoking, body mass index, C-reactive protein, and polygenic risk for specific health conditions. In sensitivity analyses that excluded somatic depression symptoms, only the association with sleep apnea remained significant (OR 1.32, 95% CI 1.09-1.60).ConclusionsA history of depression symptoms by early midlife is associated with an elevated risk for subsequent development of several self-reported health conditions. When isolated, non-somatic depression symptoms are associated with incident self-reported sleep apnea. Depression symptom history may be a predictor or marker of cardiometabolic risk over decades.

The locus coeruleus (LC) is one of the earliest sites of tau pathology, making it a key structure in early Alzheimer's disease (AD) progression. As the primary source of norepinephrine for the brain, reduced LC integrity may have negative consequences for brain health, yet macrostructural brain measures (e.g. cortical thickness) may not be sensitive to early stages of neurodegeneration. We therefore examined whether LC integrity was associated with differences in cortical gray matter microstructure among 435 men (mean age = 67.5; range = 62-71.7). LC structural integrity was indexed by contrast-to-noise ratio (LCCNR) from a neuromelanin-sensitive MRI scan. Restriction spectrum imaging (RSI), an advanced multi-shell diffusion technique, was used to characterize cortical microstructure, modeling total diffusion in restricted, hindered, and free water compartments. Higher LCCNR (greater integrity) was associated with higher hindered and lower free water diffusion in multiple cortical regions. In contrast, no associations between LCCNR and cortical thickness survived correction. Results suggest lower LC integrity is associated with patterns of cortical microstructure that may reflect a reduction in cytoarchitectural barriers due to broader neurodegenerative processes. These findings highlight the potential utility for LC imaging and advanced diffusion measures of cortical microstructure in assessing brain health and early identification of neurodegenerative processes.

Background and aimsSmoking is associated with increased risk for brain aging/atrophy and dementia. Few studies have examined early associations with brain aging. This study aimed to measure whether adult men with a history of heavier smoking in early mid-life would have older than predicted brain age 16-28 years later.DesignProspective cohort observational study, utilizing smoking pack years data from average age 40 (early mid-life) predicting predicted brain age difference scores (PBAD) at average ages 56, 62 (later mid-life) and 68 years (early old age). Early mid-life alcohol use was also evaluated.SettingPopulation-based United States sample.Participants/casesParticipants were male twins of predominantly European ancestry who served in the United States military between 1965 and 1975. Structural magnetic resonance imaging (MRI) began at average age 56. Subsequent study waves included most baseline participants; attrition replacement subjects were added at later waves.MeasurementsSelf-reported smoking information was used to calculate pack years smoked at ages 40, 56, 62, and 68. MRIs were processed with the Brain-Age Regression Analysis and Computation Utility software (BARACUS) program to create PBAD scores (chronological age-predicted brain age) acquired at average ages 56 (n = 493; 2002-08), 62 (n = 408; 2009-14) and 68 (n = 499; 2016-19).FindingsIn structural equation modeling, age 40 pack years predicted more advanced age 56 PBAD [β = -0.144, P = 0.012, 95% confidence interval (CI) = -0.257, -0.032]. Age 40 pack years did not additionally predict PBAD at later ages. Age 40 alcohol consumption, but not a smoking × alcohol interaction, predicted more advanced PBAD at age 56 (β = -0.166, P = 0.001, 95% CI = -0.261, -0.070) with additional influences at age 62 (β = -0.115, P = 0.005, 95% CI = -0.195, -0.036). Age 40 alcohol did not predict age 68 PBAD. Within-twin-pair analyses suggested some genetic mechanism partially underlying effects of alcohol, but not smoking, on PBAD.ConclusionsHeavier smoking and alcohol consumption by age 40 appears to predict advanced brain aging by age 56 in men.

Because longitudinal studies of aging typically lack cognitive data from earlier ages, it is unclear how general cognitive ability (GCA) changes throughout the life course. In 1173 Vietnam Era Twin Study of Aging (VETSA) participants, we assessed young adult GCA at average age 20 and current GCA at 3 VETSA assessments beginning at average age 56. The same GCA index was used throughout. Higher young adult GCA and better GCA maintenance were associated with stronger specific cognitive abilities from age 51 to 73. Given equivalent GCA at age 56, individuals who had higher age 20 GCA outperformed those whose GCA remained stable in terms of memory, executive function, and working memory abilities from age 51 to 73. Thus, paradoxically, despite poorer maintenance of GCA, high young adult GCA still conferred benefits. Advanced predicted brain age and the combination of elevated vascular burden and APOE-ε4 status were associated with poorer maintenance of GCA. These findings highlight the importance of distinguishing between peak and current GCA for greater understanding of cognitive aging.

Magnetic resonance imaging data are being used in statistical models to predicted brain ageing (PBA) and as biomarkers for neurodegenerative diseases such as Alzheimer's Disease. Despite their increasing application, the genetic and environmental etiology of global PBA indices is unknown. Likewise, the degree to which genetic influences in PBA are longitudinally stable and how PBA changes over time are also unknown. We analyzed data from 734 men from the Vietnam Era Twin Study of Aging with repeated MRI assessments between the ages 51-72 years. Biometrical genetic analyses "twin models" revealed significant and highly correlated estimates of additive genetic heritability ranging from 59 to 75%. Multivariate longitudinal modeling revealed that covariation between PBA at different timepoints could be explained by a single latent factor with 73% heritability. Our results suggest that genetic influences on PBA are detectable in midlife or earlier, are longitudinally very stable, and are largely explained by common genetic influences.

Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer's disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast "resilient" unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk.

Abstract Background Patients with preoperative anemia have a higher risk of requiring blood transfusion after major orthopedic surgery due to increased blood loss and closer transfusion thresholds. Various patient blood management (PBM) policies aim to reduce transfusion rates. This observational study aimed to investigate blood loss and evaluate the effectiveness of an adjusted surgical PBM protocol in patients with anemic chronic disease (ACD) undergoing elective total knee arthroplasty (TKA). Methods A consecutive cohort of patients underwent elective unilateral TKA with an adjusted PBM protocol. The protocol consisted of epoetin (EPO) alfa therapy prescribed by the surgeon, routine administration of tranexamic acid (TXA), and standardized postoperative pharmacologic prophylaxis for thromboembolism. The performance of this PBM protocol was analyzed in patients with a baseline hemoglobin level of less than 12 g/dl. Hemoglobin levels were controlled at admission, on postoperative day (POD) 1, and on POD 7 ± 1. A bleeding index (BI-7) was used as an estimate of blood loss up until POD 7. Multiple linear regression was used to assess whether there were any differences in BI-7 between ACD– and ACD + patients. Results A total of 751 patients with complete hemoglobin monitoring were included in the study. Of these patients, 68 (9.1%) had a baseline hemoglobin concentration of less than 12 g/dl (ACD group). In this group, 28 patients (41.2%) received preoperative EPO therapy. The mean adjusted BI-7 for the study population was 3.0 (95% CI, 2.9 to 3.0) g/dl in the ACD– group and 2.3 (95% CI, 2.0–2.6) g/dl in the ACD + group. The difference in BI-7 was statistically significant (difference, 0.6 [95% CI: 0.3 to 0.9] g/dl, p

We examined the influence of lifestyle on brain aging after nearly 30 years, and tested the hypothesis that young adult general cognitive ability (GCA) would moderate these effects. In the community-dwelling Vietnam Era Twin Study of Aging (VETSA), 431 largely non-Hispanic white men completed a test of GCA at mean age 20. We created a modifiable lifestyle behavior composite from data collected at mean age 40. During VETSA, MRI-based measures at mean age 68 included predicted brain age difference (PBAD), Alzheimer's disease (AD) brain signature, and abnormal white matter scores. There were significant main effects of young adult GCA and lifestyle on PBAD and the AD signature (ps ≤ 0.012), and a GCA-by-lifestyle interaction on both (ps ≤ 0.006). Regardless of GCA level, having more favorable lifestyle behaviors predicted less advanced brain age and less AD-like brain aging. Unfavorable lifestyles predicted advanced brain aging in those with lower age 20 GCA, but did not affect brain aging in those with higher age 20 GCA. Targeting early lifestyle modification may promote dementia risk reduction, especially among lower reserve individuals.

ObjectiveDistal sensory polyneuropathy (DSP) is a disabling consequence of human immunodeficiency virus (HIV), leading to poor quality of life and more frequent falls in older age. Neuropathic pain and paresthesia are prevalent symptoms; however, there are currently no known curative treatments and the longitudinal course of pain in HIV-associated DSP is poorly characterized.MethodsThis was a prospective longitudinal study of 265 people with HIV (PWH) enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study with baseline and 12-year follow-up evaluations. Since pain and paresthesia are highly correlated, statistical decomposition was used to separate the two symptoms at baseline. Multivariable logistic regression analyses of decomposed variables were used to determine the effects of neuropathy symptoms at baseline on presence and worsening of distal neuropathic pain at 12-year follow-up, adjusted for covariates.ResultsMean age was 56 ± 8 years, and 21% were female at follow-up. Nearly the entire cohort (96%) was on antiretroviral therapy (ART), and 82% had suppressed (≤50 copies/mL) plasma viral loads at follow-up. Of those with pain at follow-up (n = 100), 23% had paresthesia at the initial visit. Decomposed paresthesia at baseline increased the risk of pain at follow-up (odds ratio [OR] 1.56; 95% confidence interval [CI] 1.18, 2.07), and decomposed pain at baseline predicted a higher frequency of pain at follow-up (OR 1.96 [95% CI 1.51, 2.58]).ConclusionsParesthesias are a clinically significant predictor of incident pain at follow-up among aging PWH with DSP. Development of new therapies to encourage neuroregeneration might take advantage of this finding to choose individuals likely to benefit from treatment preventing incident pain.

Neuroimaging signatures based on composite scores of cortical thickness and hippocampal volume predict progression from mild cognitive impairment to Alzheimer's disease. However, little is known about the ability of these signatures among cognitively normal adults to predict progression to mild cognitive impairment. Towards that end, a signature sensitive to microstructural changes that may predate macrostructural atrophy should be useful. We hypothesized that: (i) a validated MRI-derived Alzheimer's disease signature based on cortical thickness and hippocampal volume in cognitively normal middle-aged adults would predict progression to mild cognitive impairment; and (ii) a novel grey matter mean diffusivity signature would be a better predictor than the thickness/volume signature. This cohort study was part of the Vietnam Era Twin Study of Aging. Concurrent analyses compared cognitively normal and mild cognitive impairment groups at each of three study waves (ns = 246-367). Predictive analyses included 169 cognitively normal men at baseline (age = 56.1, range = 51-60). Our previously published thickness/volume signature derived from independent data, a novel mean diffusivity signature using the same regions and weights as the thickness/volume signature, age, and an Alzheimer's disease polygenic risk score were used to predict incident mild cognitive impairment an average of 12 years after baseline (follow-up age = 67.2, range = 61-71). Additional analyses adjusted for predicted brain age difference scores (chronological age minus predicted brain age) to determine if signatures were Alzheimer-related and not simply ageing-related. In concurrent analyses, individuals with mild cognitive impairment had higher (worse) mean diffusivity signature scores than cognitively normal participants, but thickness/volume signature scores did not differ between groups. In predictive analyses, age and polygenic risk score yielded an area under the curve of 0.74 (sensitivity = 80.00%; specificity = 65.10%). Prediction was significantly improved with addition of the mean diffusivity signature (area under the curve = 0.83; sensitivity = 85.00%; specificity = 77.85%; P = 0.007), but not with addition of the thickness/volume signature. A model including both signatures did not improve prediction over a model with only the mean diffusivity signature. Results held up after adjusting for predicted brain age difference scores. The novel mean diffusivity signature was limited by being yoked to the thickness/volume signature weightings. An independently derived mean diffusivity signature may thus provide even stronger prediction. The young age of the sample at baseline is particularly notable. Given that the brain signatures were examined when participants were only in their 50 s, our results suggest a promising step towards improving very early identification of Alzheimer's disease risk and the potential value of mean diffusivity and/or multimodal brain signatures.

During April 5-July 8, 2022, the World Health Organization (WHO) received reports of 1,010 probable cases of severe acute hepatitis of unknown etiology (SAHUE) in young children from 35 countries [...]

Abstract Pseudarthrosis following transforaminal interbody fusion (TLIF) is not infrequent. Although cage migration and subsidence are commonly regarded as evidence of the absence of solid fusion, there is still no evidence of the influence of cage migration and subsidence on fusion. This study aimed to evaluate cage migration and subsidence using computed tomography (CT) DICOM data following lumbar interbody fusion. The effects of cage migration and subsidence on fusion and clinical outcomes were also assessed. A postoperative CT data set of 67 patients treated with monosegmental TLIF was analyzed in terms of cage position. To assess the effects of cage migration and subsidence on fusion, 12-month postoperative CT scans were used to assess fusion status. Clinical evaluation included the visual analog scale for pain and the Oswestry Disability Index. Postoperative cage migration occurred in 85.1% of all patients, and cage subsidence was observed in 58.2%. Radiological signs of pseudarthrosis was observed in 7.5% of the patients Neither cage migration nor subsidence affected the clinical or radiographic outcomes. No correlation was found between clinical and radiographic outcomes. The incidence of cage migration was considerable. However, as cage migration and subsidence were not associated with bony fusion, their clinical significance was considered limited.

IntroductionThe locus coeruleus (LC) undergoes extensive neurodegeneration in early Alzheimer's disease (AD). The LC is implicated in regulating the sleep-wake cycle, modulating cognitive function, and AD progression.MethodsParticipants were 481 men (ages 62 to 71.7) from the Vietnam Era Twin Study of Aging. LC structural integrity was indexed by neuromelanin-sensitive magnetic resonance imaging (MRI) contrast-to-noise ratio (LCCNR ). We examined LCCNR , cognition, amnestic mild cognitive impairment (aMCI), and daytime dysfunction.ResultsHeritability of LCCNR was .48. Participants with aMCI showed greater daytime dysfunction. Lower LCCNR was associated with poorer episodic memory, general verbal fluency, semantic fluency, and processing speed, as well as increased odds of aMCI and greater daytime dysfunction.DiscussionReduced LC integrity is associated with widespread differences across cognitive domains, daytime sleep-related dysfunction, and risk for aMCI. These findings in late-middle-aged adults highlight the potential of MRI-based measures of LC integrity in early identification of AD risk.

Objective: Abnormal white matter (AWM) on magnetic resonance imaging is associated with cognitive performance in older adults. We explored cognitive associations with AWM during late-midlife. Method: Participants were community-dwelling men (n = 242; M = 61.90 years; range = 56-66). Linear-mixed effects regression models examined associations of total, periventricular, and deep AWM with cognitive performance, controlling for multiple comparisons. Models considering specific cognitive domains controlled for current general cognitive ability (GCA). We hypothesized that total AWM would be associated with worse processing speed, executive function, and current GCA; deep AWM would correlate with GCA and periventricular AWM would relate to specific cognitive abilities. We also assessed the potential influence of cognitive reserve by examining a moderation effect of early life (mean age of 20) cognition. Results: Greater total and deep AWM were associated with poorer current GCA. Periventricular AWM was associated with worse executive function, working memory, and episodic memory. When periventricular and deep AWM were modeled simultaneously, both retained their respective significant associations with cognitive performance. Cognitive reserve did not moderate associations. Conclusions: Our findings suggest that AWM contributes to poorer cognitive function in late-midlife. Examining only total AWM may obscure the potential differential impact of regional AWM. Separating total AWM into subtypes while controlling for current GCA revealed a dissociation in relationships with cognitive performance; deep AWM was associated with nonspecific cognitive ability whereas periventricular AWM was associated with specific frontal-related abilities and memory. Management of vascular or other risk factors that may increase the risk of AWM should begin during or before early late-midlife. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The pathogenesis of HIV-associated neurocognitive impairment (NCI) may involve iron dysregulation. In 243 HIV-seropositive adults without severe comorbidities, we therefore genotyped 250 variants in 20 iron-related genes and evaluated their associations with magnetic resonance imaging measures of brain structure and metabolites, including measures previously linked to NCI. Multivariable regression analyses examined associations between genetic variants and neuroimaging measures, adjusting for relevant covariates and multiple testing. Exploratory analyses stratified by NCI (Global Deficit Score ≥ 0.5 vs.

Posttraumatic stress disorder (PTSD) is known to persist, eliciting early medical co-morbidity, and accelerated aging. Although PTSD diagnosis has been found to be associated with smaller volume in multiple brain regions, posttraumatic stress (PTS) symptoms and their associations with brain morphometry are rarely assessed over long periods of time. We predicted that persistent PTS symptoms across ~24 years would be inversely associated with hippocampal, amygdala, anterior cingulate volumes, and hippocampal occupancy (HOC = hippocampal volume/[hippocampal volume + inferior lateral ventricle volume]) in late middle age. Exploratory analyses examined prefrontal regions. We assessed PTS symptoms in 247 men at average ages 38 (time 1) and 62 (time 2). All were trauma-exposed prior to time 1. Brain volumes were assessed at time 2 using 3 T structural magnetic resonance imaging. Symptoms were correlated over time (r = 0.46 p

Background and purposePeriventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings.MethodsParticipants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC.ResultsIn the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype.ConclusionsOur study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

ObjectiveDistal sensory polyneuropathy (DSP) and neuropathic pain are important clinical concerns in virally suppressed people with HIV. We determined how these conditions evolved, what factors influenced their evolution, and their clinical impact.MethodsAmbulatory, community-dwelling HIV seropositive individuals were recruited at six research centers. Clinical evaluations at baseline and 12 years later determined neuropathy signs and distal neuropathic pain (DNP). Additional assessments measured activities of daily living and quality of life (QOL). Factors potentially associated with DSP and DNP progression included disease severity, treatment, demographics, and co-morbidities. Adjusted odds ratios were calculated for follow-up neuropathy outcomes.ResultsOf 254 participants, 21.3% were women, 57.5% were non-white. Mean baseline age was 43.5 years. Polyneuropathy prevalence increased from 25.7% to 43.7%. Of 173 participants initially pain-free, 42 (24.3%) had incident neuropathic pain. Baseline risk factors for incident pain included unemployment (OR [95% CI], 5.86 [1.97, 17.4]) and higher baseline body mass index (BMI) (1.78 [1.03, 3.19] per 10-units). Participants with neuropathic pain at follow-up had significantly worse QOL and greater dependence in activities of daily living than those who remained pain-free.InterpretationHIV DSP and neuropathic pain increased in prevalence and severity over 12 years despite high rates of viral suppression. The high burden of neuropathy included disability and poor life quality. However, substantial numbers remained pain-free despite clear evidence of neuropathy on exam. Protective factors included being employed and having a lower BMI. Implications for clinical practice include promotion of lifestyle changes affecting reversible risk factors.