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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.

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.

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.

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.

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.

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.

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.

ObjectiveFrascati international research criteria for HIV-associated neurocognitive disorders (HAND) are controversial; some investigators have argued that Frascati criteria are too liberal, resulting in a high false positive rate. Meyer et al. recommended more conservative revisions to HAND criteria, including exploring other commonly used methodologies for neurocognitive impairment (NCI) in HIV including the global deficit score (GDS). This study compares NCI classifications by Frascati, Meyer, and GDS methods, in relation to neuroimaging markers of brain integrity in HIV.MethodTwo hundred forty-one people living with HIV (PLWH) without current substance use disorder or severe (confounding) comorbid conditions underwent comprehensive neurocognitive testing and brain structural magnetic resonance imaging and magnetic resonance spectroscopy. Participants were classified using Frascati criteria versus Meyer criteria: concordant unimpaired [Frascati(Un)/Meyer(Un)], concordant impaired [Frascati(Imp)/Meyer(Imp)], or discordant [Frascati(Imp)/Meyer(Un)] which were impaired via Frascati criteria but unimpaired via Meyer criteria. To investigate the GDS versus Meyer criteria, the same groupings were utilized using GDS criteria instead of Frascati criteria.ResultsWhen examining Frascati versus Meyer criteria, discordant Frascati(Imp)/Meyer(Un) individuals had less cortical gray matter, greater sulcal cerebrospinal fluid volume, and greater evidence of neuroinflammation (i.e., choline) than concordant Frascati(Un)/Meyer(Un) individuals. GDS versus Meyer comparisons indicated that discordant GDS(Imp)/Meyer(Un) individuals had less cortical gray matter and lower levels of energy metabolism (i.e., creatine) than concordant GDS(Un)/Meyer(Un) individuals. In both sets of analyses, the discordant group did not differ from the concordant impaired group on any neuroimaging measure.ConclusionsThe Meyer criteria failed to capture a substantial portion of PLWH with brain abnormalities. These findings support continued use of Frascati or GDS criteria to detect HIV-associated CNS dysfunction.

BackgroundLarge-scale brain networks such as the default mode network (DMN) are often disrupted in Alzheimer's disease (AD). Numerous studies have examined DMN functional connectivity in those with mild cognitive impairment (MCI), a presumed AD precursor, to discover a biomarker of AD risk. Prior reviews were qualitative or limited in scope or approach.ObjectiveWe aimed to systematically and quantitatively review DMN resting state fMRI studies comparing MCI and healthy comparison (HC) groups.MethodsPubMed was searched for relevant articles. Study characteristics were abstracted and the number of studies showing no group difference or hyper- versus hypo-connnectivity in MCI was tallied. A voxel-wise (ES-SDM) meta-analysis was conducted to identify regional group differences.ResultsQualitatively, our review of 57 MCI versus HC comparisons suggests substantial inconsistency; 9 showed no group difference, 8 showed MCI > HC and 22 showed HC > MCI across the brain, and 18 showed regionally-mixed directions of effect. The meta-analysis of 31 studies revealed areas of significant hypo- and hyper-connectivity in MCI, including hypoconnectivity in the posterior cingulate cortex/precuneus (z = -3.1, p

Evidence strongly suggests that being overweight or obese at midlife confers significantly higher risk for Alzheimer's disease and greater brain atrophy later in life. Few studies, however, examine associations between longitudinal changes in adiposity during early adulthood and later brain morphometry. Measures of body mass index (BMI) were collected in 373 men from the Vietnam Era Twin Study of Aging at average ages 20, 40, 56, and 62 years, yielding 2 BMI trajectories. We then examined associations between BMI phenotypes (trajectories, continuous BMI, obese/nonobese), cortical thickness, and white matter measures from structural magnetic resonance imaging at mean age 62 (time 4, range 56-66 years). Those on the obesity trajectory (N = 171) had a thinner cortex compared with the normal/lean trajectory (N = 202) in multiple frontal and temporal lobe bilateral regions of interest: superior, inferior, middle temporal gyri, temporal pole, fusiform gyrus, banks of the superior temporal sulcus, frontal pole, pars triangularis, caudal and rostral middle frontal gyri (all p < 0.05, false discovery rate corrected). Frontal lobe thinness tended to occur mainly in the right hemisphere. Results were similar for obese versus nonobese adults at age 62. There were no significant differences for white matter volume or abnormalities. Taken in the context of other research, these associations between brain structures and excess BMI at midlife suggest potential for increased risk for cognitive decline in later life.

ObjectiveThe influence of confounding neurocognitive comorbidities in people living with HIV (PLWH) on neuroimaging has not been systematically evaluated. We determined associations between comorbidity burden and brain integrity and examined the moderating effect of age on these relationships.DesignObservational, cross-sectional substudy of the CNS HIV Antiretroviral Therapy Effects Research cohort.MethodsA total of 288 PLWH (mean age = 44.2) underwent structural MRI and magnetic resonance spectroscopy as well as neurocognitive and neuromedical assessments. Consistent with Frascati criteria for HIV-associated neurocognitive disorders (HAND), neuromedical and neuropsychiatric comorbidity burden was classified as incidental (mild), contributing (moderate), or confounding (severe-exclusionary) to a diagnosis of HAND. Multiple regression modeling predicted neuroimaging outcomes as a function of comorbidity classification, age, and their interaction.ResultsComorbidity classifications were 176 incidental, 77 contributing, and 35 confounded; groups did not differ in HIV disease characteristics. Relative to incidental and contributing participants, confounded participants had less cortical gray matter and more abnormal white matter and ventricular cerebrospinal fluid, alongside more neuroinflammation (choline, myo-inositol) and less neuronal integrity (N-acetylaspartate). Older age exacerbated the impact of comorbidity burden: to a greater extent in the confounded group, older age was associated with more abnormal white matter (P = 0.017), less total white matter (P = 0.015), and less subcortical gray matter (P = 0.014).ConclusionNeuroimaging in PLWH reveals signatures associated with confounding neurocognitive conditions, emphasizing the importance of evaluating these among individuals with suspected HAND. Older age amplifies subcortical and white matter tissue injury, especially in PLWH with severe comorbidity burden, warranting increased attention to this population as it ages.

The human hippocampus can be subdivided into subfields with unique functional properties and differential vulnerability to disease or neuropsychiatric conditions. Identifying genes that confer susceptibility to such processes is an important goal in developing treatments. Recent advances in automatic subfield segmentation from magnetic resonance images make it possible to use these measures as phenotypes in large-scale genome-wide association studies. Such analyses are likely to rely largely on standard resolution (~1 mm isotropic) T1 -weighted images acquired on 3.0T scanners. Determining whether the genetic architecture of subfields can be detected from such images is therefore an important step. We used Freesurfer v6.0 to segment hippocampal subfields in two large twin studies, the Vietnam Era Twin Study of Aging and the Human Connectome Project. We estimated heritability of subfields and the genetic overlap with total hippocampal volume. Heritability was similar across samples, but little genetic variance remained after accounting for genetic influences on total hippocampal volume. Importantly, we examined genetic relationships between subfields to determine whether subfields can be grouped based on a smaller number of underlying, genetically independent factors. We identified three genetic factors in both samples, but the high degree of cross loadings precluded formation of genetically distinct groupings of subfields. These results confirm the reliability of Freesurfer v6.0 generated subfields across samples for phenotypic analyses. However, the current results suggest that it will be difficult for large-scale genetic analyses to identify subfield-specific genes that are distinct from both total hippocampal volume and other subfields using segmentations generated from standard resolution T1 -weighted images.

How and when education improves cognitive capacity is an issue of profound societal importance. Education and later-life education-related factors, such as occupational complexity and engagement in cognitive-intellectual activities, are frequently considered indices of cognitive reserve, but whether their effects are truly causal remains unclear. In this study, after accounting for general cognitive ability (GCA) at an average age of 20 y, additional education, occupational complexity, or engagement in cognitive-intellectual activities accounted for little variance in late midlife cognitive functioning in men age 56-66 (n = 1009). Age 20 GCA accounted for 40% of variance in the same measure in late midlife and approximately 10% of variance in each of seven cognitive domains. The other factors each accounted for

HIV-associated neurocognitive disorders (HANDs) persist even with virologic suppression on combination antiretroviral therapy (cART), and the underlying pathophysiological mechanisms are not well understood. We performed structural magnetic resonance imaging and MR spectroscopy (MRS) in HIV+ individuals without major neurocognitive comorbidities. Study participants were classified as neurocognitively unimpaired (NU), asymptomatic (ANI), mild neurocognitive disorder (MND), or HIV-associated dementia (HAD). Using structural MRI, we measured volumes of cortical and subcortical gray matter and total and abnormal white matter (aWM). Using single-voxel MRS, we estimated metabolites in frontal gray matter (FGM) and frontal white matter (FWM) and basal ganglia (BG) regions. Adjusted odds ratios were used to compare HAND to NU. Among 253 participants, 40% met HAND criteria (21% ANI, 15% MND, and 4% HAD). Higher risk of HAND was associated with more aWM. Both HAD and MND also had smaller gray and white matter volumes than NU. Among individuals with undetectable plasma HIV RNA, structural volumetric findings were similar to the overall sample. MND had lower FWM creatine and higher FGM choline relative to NU, whereas HAD and ANI had lower BG N-acetyl aspartate relative to NU. In the virologically suppressed subgroup, however, ANI and MND had higher FGM choline compared to NU. Overall, HAND showed specific alterations (more aWM and inflammation; less gray matter volume and lower NAA). Some MR measures differentiated less severe subtypes of HAND from HAD. These MR alterations may represent legacy effects or accumulating changes, possibly related to medical comorbidities, antiretroviral therapy, or chronic effects of HIV brain infection.

Individual differences in white matter tract microstructure, measured with diffusion tensor imaging (DTI), demonstrate substantial heritability. However, it is unclear to what extent this heritability reflects global genetic influences or tract-specific genetic influences. The goal of the current study was to quantify the proportion of genetic and environmental variance in white matter tracts attributable to global versus tract-specific influences. We assessed fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) across 11 tracts and 22 subdivisions of these tracts in 392 middle-aged male twins from the Vietnam Era Twin Study of Aging (VETSA). In principal component analyses of the 11 white matter tracts, the first component, which represents the global signal, explained 50.1% and 62.5% of the variance in FA and MD, respectively. Similarly, the first principal component of the 22 tract subdivisions explained 38.4% and 47.0% of the variance in FA and MD, respectively. Twin modeling revealed that DTI measures of all tracts and subdivisions were heritable, and that genetic influences on global FA and MD accounted for approximately half of the heritability in the tracts or tract subdivisions. Similar results were observed for the AD and RD diffusion metrics. These findings underscore the importance of controlling for DTI global signals when measuring associations between specific tracts and outcomes such as cognitive ability, neurological and psychiatric disorders, and brain aging.

Height and general cognitive ability are positively associated, but the underlying mechanisms of this relationship are not well understood. Both height and general cognitive ability are positively associated with brain size. Still, the neural substrate of the height-cognitive ability association is unclear. We used a sample of 515 middle-aged male twins with structural magnetic resonance imaging data to investigate whether the association between height and cognitive ability is mediated by cortical size. In addition to cortical volume, we used genetically, ontogenetically and phylogenetically distinct cortical metrics of total cortical surface area and mean cortical thickness. Height was positively associated with general cognitive ability and total cortical volume and cortical surface area, but not with mean cortical thickness. Mediation models indicated that the well-replicated height-general cognitive ability association is accounted for by individual differences in total cortical volume and cortical surface area (highly heritable metrics related to global brain size), and that the genetic association between cortical surface area and general cognitive ability underlies the phenotypic height-general cognitive ability relationship.

Negative fateful life events (FLEs) such as interpersonal conflict, death in the family, financial hardship, and serious medical emergencies can act as allostatic stressors that accelerate biological aging. However, the relationship between FLEs and neuroanatomical aging is not well understood. We examined 359 men (mean age 62 years) participating in the Vietnam Era twin study of aging (VETSA) to determine whether negative midlife FLEs are associated with advanced brain aging after controlling for physical, psychological, and lifestyle factors. At two different time points, participants were assessed for negative FLEs, health and well-being, general cognitive ability, socioeconomic status, depression, and ethnicity. Participants underwent a magnetic resonance imaging examination, and T1-weighted images were processed with FreeSurfer. Subsequent neuroanatomical measurements were entered into the Brain-Age Regression Analysis and Computation Utility software (BARACUS) to predict brain age. Having more midlife FLEs, particularly relating to interpersonal relationships, was associated with advanced predicted brain aging (i.e., higher predicted brain age relative to chronological age). This association remained after controlling for the significant covariates of alcohol consumption, cardiovascular risk, adult socioeconomic status, and ethnicity.

Two basic neuroimaging-based characterizations of white matter tracts are the magnitude of water diffusion along the principal tract orientation (axial diffusivity, AD) and water diffusion perpendicular to the principal orientation (radial diffusivity, RD). It is generally accepted that decreases in AD reflect disorganization, damage, or loss of axons, whereas increases in RD are indicative of disruptions to the myelin sheath. Previous reports have detailed the heritability of individual AD and RD measures, but have not examined the extent to which the same or different genetic or environmental factors influence these two phenotypes (except for corpus callosum). We implemented bivariate twin analyses to examine the shared and independent genetic influences on AD and RD. In the Vietnam Era Twin Study of Aging, 393 men (mean age = 61.8 years, SD = 2.6) underwent diffusion-weighted magnetic resonance imaging. We derived fractional anisotropy (FA), mean diffusivity (MD), AD, and RD estimates for 11 major bilateral white matter tracts and the mid-hemispheric corpus callosum, forceps major, and forceps minor. Separately, AD and RD were each highly heritable. In about three-quarters of the tracts, genetic correlations between AD and RD were >.50 (median = .67) and showed both unique and common variance. Genetic variance of FA and MD were predominately explained by RD over AD. These findings are important for informing genetic association studies of axonal coherence/damage and myelination/demyelination. Thus, genetic studies would benefit from examining the shared and unique contributions of AD and RD.

Heavy alcohol consumption is associated with deleterious changes in the brain but associations of moderate alcohol intake are not well understood. We examined the association of alcohol consumption with brain white matter health in 377 middle-aged men (56-66 years old; mean 61.8 ± 2.6 years) who were participants in the Vietnam Era Twin Study of Aging (VETSA). T1-, T2-, proton density-, and diffusion-weighted magnetic resonance images were obtained. Diffusion measures were quantified from 12 major white matter tracts. Global white matter lesion (WML) burden was also quantified. Mixed effects linear models examined differences in diffusivity and WMLs by amount of alcohol intake. Analyses adjusted for numerous demographic, health, and lifestyle variables. An inverted-U association was found between alcohol intake and fractional anisotropy (FA) in several tracts, including the inferior-frontal-occipital fasciculus, uncinate fasciculus, superior longitudinal fasciculus, the forceps minor and the anterior thalamic radiations. In these tracts, FA increased with increasing alcohol intake, peaking with moderate alcohol intake (9-28 drinks in 14 days), and declining with heavier intake. Associations remained significant after exclusion of individuals with diabetes or hypertension. There was a U-shaped association in WML burden with highest burden among never drinkers and heavy drinkers (>28 drinks in 14 days). This association was no longer significant after exclusion of individuals with hypertension, since WML burden among heavy drinkers no longer differed from that of other drinkers. This suggests that hypertension related to heavy alcohol intake may contribute to WML burden observed among heavy drinkers. Together, these correlational results suggest that among middle-aged men, moderate drinking may be associated with metrics of better white matter health, particularly microstructural measures, whereas drinking beyond recommended guidelines may be associated with both microstructural and macrostructural white matter damage.

ObjectiveThis study examined the effects of HIV infection, methamphetamine dependence and their interaction on cortical thickness, area and volume, as well as the potential interactive effects on cortical morphometry of HIV and methamphetamine with age.MethodT1-weighted structural images were obtained on a 3.0T General Electric MR750 scanner. Freesurfer v5.3.0 was used to derive cortical thickness, area and volume measures in thirty-four regions based on Desikan-Killiany atlas labels.ResultsFollowing correction for multiple statistical tests, HIV diagnosis was not significantly related to cortical thickness or area in any ROI, although smaller global cortical area and volume were seen in those with lower nadir CD4 count. HIV diagnosis, nevertheless, was associated with smaller mean cortical volumes in rostral middle frontal gyrus and in the inferior and superior parietal lobes. Methamphetamine dependence was significantly associated with thinner cortex especially in posterior cingulate gyrus, but was not associated with cortical area or volume following correction for multiple statistical tests. We found little evidence that methamphetamine dependence moderated differences in cortical area, volume or thickness for any ROI in the HIV seropositive group. Interactions with age revealed that HIV diagnosis attenuated the degree of age-related cortical thinning seen in non-infected individuals; intercepts indicated that young HIV seropositive individuals had thinner cortex than non-infected peers.ConclusionsMethamphetamine dependence does not appear to potentiate a reduction of cortical area, volume or thickness in HIV seropositive individuals. The finding of thinner cortex in young HIV seropositive individuals and the association between CD4 nadir and global cortical area and volume argue for prioritizing early antiretroviral treatment.

Pupillary responses during cognitive tasks are linked to functioning of the locus coeruleus (LC). The LC is an early site of abnormal tau deposition, which may contribute to key aspects of Alzheimer's disease (AD) pathophysiology. We previously found attenuation of pupillary responses to increases in cognitive load in individuals with mild cognitive impairment (MCI), suggesting pupillary responses may provide a biomarker of early risk for AD associated with LC dysfunction. The LC modulates cortical activity through two modes of operation: tonic and phasic. Early LC damage has been predicted to result in a state of persistent high tonic LC activity that may disrupt task-related phasic activity. To further examine whether pupillary responses are associated with early LC dysfunction, we measured pupil dilation during a digit span task as a measure of phasic activity, and low frequency BOLD variance (LFBV) during resting-state fMRI in key nodes of the ventral attention network (VAN) as a measure of cortical reactivity related to LC tonic activity in 358 middle-aged men. Individuals with greater LFBV in VAN nodes, i.e., higher tonic brain activity at rest, showed a smaller increase in pupil dilation from low to moderate cognitive loads. Thus, higher tonic LFBV activity at rest was related to reduced task-appropriate phasic dilation increases. The results support predictions from prominent models of LC functioning in which early LC dysfunction leads to persistent high tonic rates of activity during rest and lower signal-to-noise of phasic responses during task performance. Taken together with previous findings of early AD pathophysiology in LC and reduced phasic dilation responses to increased cognitive load in individuals with MCI, the present results suggest that pupillary responses may index early LC dysfunction and should receive further study as a potential biomarker of risk for AD.

Increased mean diffusivity (MD) is hypothesized to reflect tissue degeneration and may provide subtle indicators of neuropathology as well as age-related brain changes in the absence of volumetric differences. Our aim was to determine the degree to which genetic and environmental variation in subcortical MD is distinct from variation in subcortical volume. Data were derived from a sample of 387 male twins (83 MZ twin pairs, 55 DZ twin pairs, and 111 incomplete twin pairs) who were MRI scanned as part of the Vietnam Era Twin Study of Aging. Quantitative estimates of MD and volume for 7 subcortical regions were obtained: thalamus, caudate nucleus, putamen, pallidum, hippocampus, amygdala, and nucleus accumbens. After adjusting for covariates, bivariate twin models were fitted to estimate the size and significance of phenotypic, genotypic, and environmental correlations between MD and volume at each subcortical region. With the exception of the amygdala, familial aggregation in MD was entirely explained by additive genetic factors across all subcortical regions with estimates ranging from 46 to 84%. Based on bivariate twin modeling, variation in subcortical MD appears to be both genetically and environmentally unrelated to individual differences in subcortical volume. Therefore, subcortical MD may be an alternative biomarker of brain morphology for complex traits worthy of future investigation. Hum Brain Mapp 38:2589-2598, 2017. © 2017 Wiley Periodicals, Inc.

There is evidence that differences among individuals in white matter microstructure, as measured with diffusion tensor imaging (DTI), are under genetic control. However, little is known about the relative contribution of genetic and environmental effects on different diffusivity indices among late middle-aged adults. Here, we examined the magnitude of genetic influences for fractional anisotropy (FA), and mean (MD), axial (AD), and radial (RD) diffusivities in male twins aged 56-66 years old. Using an atlas-based registration approach to delineate individual white matter tracts, we investigated mean DTI-based indices within the corpus callosum, 12 bilateral tracts and all these regions of interest combined. All four diffusivity indices had high heritability at the global level (72%-80%). The magnitude of genetic effects in individual tracts varied from 0% to 82% for FA, 0% to 81% for MD, 8% to 77% for AD, and 0% to 80% for RD with most of the tracts showing significant heritability estimates. Despite the narrow age range of this community-based sample, age was correlated with all four diffusivity indices at the global level. In sum, all diffusion indices proved to have substantial heritability for most of the tracts and the heritability estimates were similar in magnitude for different diffusivity measures. Future studies could aim to discover the particular set of genes that underlie the significant heritability of white matter microstructure. Hum Brain Mapp 38:2026-2036, 2017. © 2017 Wiley Periodicals, Inc.

Objective. Despite modern antiretroviral therapy, HIV-associated neuropathy is one of the most prevalent, disabling and treatment-resistant complications of HIV disease. The presence and intensity of distal neuropathic pain is not fully explained by the degree of peripheral nerve damage. A better understanding of brain structure in HIV distal neuropathic pain may help explain why some patients with HIV neuropathy report pain while the majority does not. Previously, we reported that more intense distal neuropathic pain was associated with smaller total cerebral cortical gray matter volumes. The objective of this study was to determine which parts of the cortex are smaller.Methods. HIV positive individuals with and without distal neuropathic pain enrolled in the multisite (N = 233) CNS HIV Antiretroviral Treatment Effects (CHARTER) study underwent structural brain magnetic resonance imaging. Voxel-based morphometry was used to investigate regional brain volumes in these structural brain images.Results. Left ventral posterior cingulate cortex was smaller for HIV positive individuals with versus without distal neuropathic pain (peak P  = 0.017; peak t = 5.15; MNI coordinates x = -6, y = -54, z = 20). Regional brain volumes within cortical gray matter structures typically associated with pain processing were also smaller for HIV positive individuals having higher intensity ratings of distal neuropathic pain.Conclusions. The posterior cingulate is thought to be involved in inhibiting the perception of painful stimuli. Mechanistically a smaller posterior cingulate cortex structure may be related to reduced anti-nociception contributing to increased distal neuropathic pain.

Magnetic resonance imaging (MRI) has become an important tool in the early detection of age-related and neuropathological brain changes. Recent studies suggest that changes in mean diffusivity (MD) of cortical gray matter derived from diffusion MRI scans may be useful in detecting early effects of Alzheimer's disease (AD), and that these changes may be detected earlier than alterations associated with standard structural MRI measures such as cortical thickness. Thus, due to its potential clinical relevance, we examined the genetic and environmental influences on cortical MD in middle-aged men to provide support for the biological relevance of this measure and to guide future gene association studies. It is not clear whether individual differences in cortical MD reflect neuroanatomical variability similarly detected by other MRI measures, or whether unique features are captured. For instance, variability in cortical MD may reflect morphological variability more commonly measured by cortical thickness. Differences among individuals in cortical MD may also arise from breakdowns in myelinated fibers running through the cortical mantle. Thus, we investigated whether genetic influences on variation in cortical MD are the same or different from those influencing cortical thickness and MD of white matter (WM) subjacent to the cortical ribbon. Univariate twin analyses indicated that cortical MD is heritable in the majority of brain regions; the average of regional heritability estimates ranged from 0.38 in the cingulate cortex to 0.66 in the occipital cortex, consistent with the heritability of other MRI measures of the brain. Trivariate analyses found that, while there was some shared genetic variance between cortical MD and each of the other two measures, this overlap was not complete (i.e., the correlation was statistically different from 1). A significant amount of distinct genetic variance influences inter-individual variability in cortical MD; therefore, this measure could be useful for further investigation in studies of neurodegenerative diseases and gene association studies.

The criteria for differentiating symptomatic from asymptomatic HIV-associated neurocognitive disorder require evaluation of (1) cognitive impairment, (2) daily functioning declines, and (3) whether the functional declines are attributable to cognitive versus physical problems. Many providers rely only on self-report to evaluate these latter criteria. However, the accuracy of patient-provided information may be limited. This study evaluated the validity of self-assessment for HIV-associated neurocognitive disorder (HAND) diagnoses by comparing objective findings with self-report of criteria 2 and 3 above. Self-reports were used to stratify 277 cognitively impaired HIV+ individuals into functionally dependent (n = 159) and independent (n = 118) groups, followed by group comparisons of objective functional problems. The dependent group was then divided into those who self-attributed their functional dependence to only cognitive (n = 80) versus only physical (n = 79) causes, for further comparisons on objective findings. The functionally dependent group was significantly worse than the independent group on all objective disability characteristics except severity of cognitive impairment, while those who attributed their dependence to physical (versus cognitive) factors were similar on all objective physical, cognitive, and functioning variables. Of note, 28 % of physical attributors showed no physical abnormalities on neuromedical examinations. Results suggest that patient report is consistently associated with objective measures of functional loss; in contrast, patient identification of physical versus cognitive causes is poorly associated with objective criteria. These findings caution against relying solely on patient self-report to determine whether functional disability in cognitively impaired HIV+ individuals can be attributed to strictly physical causes.

Previous neuroimaging studies suggest a negative relationship between the apolipoprotein (ApoE) ε4 allele and brain integrity in human immunodeficiency virus (HIV)-infected (HIV+) individuals, although the presence of this relationship across adulthood remains unclear. The purpose of this study is to clarify the discrepancies using a large, diverse group of HIV+ individuals and multiple imaging modalities sensitive to HIV. The association of ApoE ε4 with structural neuroimaging and magnetic resonance spectroscopy (MRS) was examined in 237 HIV+ individuals in the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study. Cortical and subcortical gray matter, abnormal and total white matter, ventricles, sulcal cerebrospinal fluid (CSF), and cerebellar gray matter, white matter, and CSF volumes, and MRS concentrations of myo-inositol, creatine, N-acetyl-aspartate, and choline in the frontal white matter (FWM), frontal gray matter (FGM), and basal ganglia were examined. Secondary analyses explored this relationship separately in individuals ≥50 years old (n = 173) and

Prospective memory (PM) is associated with antiretroviral (ARV) adherence in HIV, but little is known about how pill burden and age might affect this association. One hundred seventeen older (≥50 years) and 82 younger (

BackgroundThe Veterans Aging Cohort Study (VACS) Index, a composite marker of disease severity among human immunodeficiency virus (HIV)-infected persons, has been associated with concurrent risk for neurocognitive impairment (NCI). The present study examined whether the VACS Index predicts longitudinal neurocognitive change.MethodsParticipants included 655 HIV-infected persons followed for up to 6 years in cohort studies at the University of California, San Diego, HIV Neurobehavioral Research Program (mean age at baseline, 42.5 years; 83% male; 60% white; AIDS in 67%; median current CD4(+) T-cell count, 346/μL; 61% receiving antiretroviral therapy). The VACS Index was calculated through standard methods. Participants completed a comprehensive neurocognitive battery. Neurocognitive status was plotted over time using demographically and practice-adjusted global and domain T scores. NCI was defined by global deficit scores derived from T scores.ResultsBaseline VACS Index scores were not predictive of changes in global T scores during the follow-up period (P = .14). However, in time-dependent analyses adjusting for covariates, higher VACS Index scores were significantly associated with worse global and domain neurocognitive performance (Ps < .01), as well as increased risk for developing NCI in a subgroup of persons who were neurocognitively normal at baseline (hazard ratio [HR], 1.17; P < .001). We categorized VACS Index scores by quartiles and found that the upper-quartile group was significantly more likely to develop NCI than the lower quartile (HR, 2.16; P < .01) and middle groups (HR, 1.76; P < .01).ConclusionsChanges in VACS Index scores correspond to changes in neurocognitive function. HIV-infected persons with high VACS Index scores are at increased risk for decline and incident NCI. The VACS Index shows promise as a tool for identifying HIV-infected persons at risk for NCI.

General cognitive ability (GCA) has substantial explanatory power for behavioral and health outcomes, but its cortical substrate is still not fully established. GCA is highly polygenic and research to date strongly suggests that its cortical substrate is highly polyregional. We show in map-based and region-of-interest-based analyses of adult twins that a complex cortical configuration underlies GCA. Having relatively greater surface area in evolutionary and developmentally high-expanded prefrontal, lateral temporal, and inferior parietal regions is positively correlated with GCA, whereas relatively greater surface area in low-expanded occipital, medial temporal, and motor cortices is negatively correlated with GCA. Essentially the opposite pattern holds for relative cortical thickness. The phenotypic positive-to-negative gradients in our cortical-GCA association maps were largely driven by a similar pattern of genetic associations. The patterns are consistent with regional cortical stretching whereby relatively greater surface area is related to relatively thinner cortex in high-expanded regions. Thus, the typical "bigger is better" view does not adequately capture cortical-GCA associations. Rather, cognitive ability is influenced by complex configurations of cortical development patterns that are strongly influenced by genetic factors. Optimal cognitive ability appears to be driven both by the absolute size and the polyregional configuration of the entire cortex rather than by small, circumscribed regions.

A wide spectrum of neurocognitive deficits characterises HIV infection in adults. HIV infection is additionally associated with morphological brain abnormalities affecting neural substrates that subserve neurocognitive function. Early life stress (ELS) also has a direct influence on brain morphology. However, the combined impact of ELS and HIV on brain structure and neurocognitive function has not been examined in an all-female sample with advanced HIV disease. The present study examined the effects of HIV and childhood trauma on brain morphometry and neurocognitive function. Structural data were acquired using a 3T Magnetom MRI scanner, and a battery of neurocognitive tests was administered to 124 women: HIV-positive with ELS (n = 32), HIV-positive without ELS (n = 30), HIV-negative with ELS (n = 31) and HIV-negative without ELS (n = 31). Results revealed significant group volumetric differences for right anterior cingulate cortex (ACC), bilateral hippocampi, corpus callosum, left and right caudate and left and right putamen. Mean regional volumes were lowest in HIV-positive women with ELS compared to all other groups. Although causality cannot be inferred, findings also suggest that alterations in the left frontal lobe, right ACC, left hippocampus, corpus callosum, left and right amygdala and left caudate may be associated with poorer neurocognitive performance in the domains of processing speed, attention/working memory, abstraction/executive functions, motor skills, learning and language/fluency with these effects more pronounced in women living with both HIV and childhood trauma. This study highlights the potential contributory role of childhood trauma to brain alterations and neurocognitive decline in HIV-infected individuals.