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BACKGROUND: Peak-width of skeletonized mean diffusivity (PSMD), a neuroimaging marker of cerebral small vessel disease (SVD), has shown excellent instrumental properties. Here, we extend our work to perform a biological validation of PSMD. METHODS: We included 396 participants from the Biomarkers for Vascular Contributions to Cognitive Impairment and Dementia (MarkVCID-1) Consortium and three replication samples (Cohorts for Heart and Aging Research in Genomic Epidemiology = 6172, Rush University Medical Center = 287, University of California Davis Alzheimers Disease Research Center = 567). PSMD was derived from diffusion tensor imaging using an automated algorithm. We related PSMD to a composite measure of general cognitive function using linear regression models adjusting for confounders. RESULTS: Higher PSMD was associated with lower general cognition in MarkVCID-1 independent of age, sex, education, and intracranial volume (Beta [95% confidence interval], -0.8 [-1.2, -0.4], P

ObjectiveOur objective was to investigate the overall and sex-specific relationships between the presence and severity of knee osteoarthritis (KOA) and muscle composition, power, and energetics in older adults.MethodsMale and female patients (n = 655, mean ± SD age 76.1 ± 4.9 years; 57% female) enrolled in the Study of Muscle, Mobility, and Aging completed standing knee radiographs and knee pain assessments. Participants were divided into three groups using Kellgren-Lawrence grade (KLG) of KOA severity (0-1, 2, or 3-4). Outcome measures included whole-body muscle mass, thigh fat-free muscle (FFM) volume and muscle fat infiltration (MFI), leg power, specific power (power normalized to muscle volume), and muscle mitochondrial energetics.ResultsOverall, the presence and severity of KOA is associated with greater MFI, lower leg power and specific power, and reduced oxidative phosphorylation (P trend < 0.036). Sex-specific analysis revealed reduced energetics only in female patients with KOA (P trend < 0.007) compared to female patients without KOA. In models adjusted for age, sex, race, nonsteroidal anti-inflammatory drug administration, site or technician, physical activity, height, and participants with abdominal adiposity with KLG 3 to 4 had greater MFI (mean 0.008%, 95% confidence interval [CI] 0.004%-0.011%) and lower leg power (mean -51.56 W, 95% CI -74.03 to -29.10 W) and specific power (mean -5.38 W/L, 95% CI -7.31 to -3.45 W/L) than those with KLG 0 to 1. No interactions were found between pain and KLG status. Among those with KOA, MFI and oxidative phosphorylation were associated with thigh FFM volume, leg power, and specific power.ConclusionMuscle health is associated with the presence and severity of KOA and differs by sex. Although muscle composition and power are lower in both male and female patients with KOA, regardless of pain status, mitochondrial energetics is reduced only in female patients.

The human face plays a central role in emotions and social communication. The emotional and somatic motor networks generate facial behaviors, but whether facial behaviors have representations in the structural anatomy of the human brain is unknown. We coded 16 facial behaviors in 55 healthy older adults who viewed five videos that elicited emotions and examined whether individual differences in facial behavior were related to regional variation in gray matter volume. Voxel-based morphometry analyses revealed that greater emotional facial behavior during the disgust trial (i.e. greater brow furrowing and eye tightening as well as nose wrinkling and upper lip raising) and the amusement trial (i.e. greater smiling and eye tightening) was associated with larger gray matter volume in midcingulate cortex, supplementary motor area, and precentral gyrus, areas spanning both the emotional and somatic motor networks. When measured across trials, however, these facial behaviors (and others) only related to gray matter volume in the precentral gyrus, a somatic motor network hub. These findings suggest that the emotional and somatic motor networks store structural representations of facial behavior and that the midcingulate cortex is critical for generating the predictable movements in the face that arise during emotions.

IntroductionCardiovascular health is important for brain aging, yet its role in the clinical manifestation of autosomal dominant or atypical forms of dementia has not been fully elucidated. We examined relationships between Life's Simple 7 (LS7) and clinical trajectories in individuals with autosomal dominant frontotemporal lobar degeneration (FTLD).MethodsTwo hundred forty-seven adults carrying FTLD pathogenic genetic variants (53% asymptomatic) and 189 non-carrier controls completed baseline LS7, and longitudinal neuroimaging and neuropsychological testing.ResultsAmong variant carriers, higher baseline LS7 is associated with slower accumulation of frontal white matter hyperintensities (WMHs), as well as slower memory and language declines. Higher baseline LS7 associated with larger baseline frontotemporal volume, but not frontotemporal volume trajectories.DiscussionBetter baseline cardiovascular health related to slower cognitive decline and accumulation of frontal WMHs in autosomal dominant FTLD. Optimizing cardiovascular health may be an important modifiable approach to bolster cognitive health and brain integrity in FTLD.HighlightsBetter cardiovascular health associates with slower cognitive decline in frontotemporal lobar degeneration (FTLD). Lifestyle relates to the accumulation of frontal white matter hyperintensities in FTLD. More optimal cardiovascular health associates with greater baseline frontotemporal lobe volume. Optimized cardiovascular health relates to more favorable outcomes in genetic dementia.

Wildlife tagging provides critical insights into animal movement ecology, physiology, and behavior amid global ecosystem changes. However, the stress induced by capture, handling, and tagging can impact post-release locomotion and activity and, consequently, the interpretation of study results. Here, we analyze post-tagging effects on 1585 individuals of 42 terrestrial mammal species using collar-collected GPS and accelerometer data. Species-specific displacements and overall dynamic body acceleration, as a proxy for activity, were assessed over 20 days post-release to quantify disturbance intensity, recovery duration, and speed. Differences were evaluated, considering species-specific traits and the human footprint of the study region. Over 70% of the analyzed species exhibited significant behavioral changes following collaring events. Herbivores traveled farther with variable activity reactions, while omnivores and carnivores were initially less active and mobile. Recovery duration proved brief, with alterations diminishing within 4-7 tracking days for most species. Herbivores, particularly males, showed quicker displacement recovery (4 days) but slower activity recovery (7 days). Individuals in high human footprint areas displayed faster recovery, indicating adaptation to human disturbance. Our findings emphasize the necessity of extending tracking periods beyond 1 week and particular caution in remote study areas or herbivore-focused research, specifically in smaller mammals.

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD-associated regional degeneration patterns relate to regional gene expression of human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroimaging from patients with FTLD and human brain regional transcriptomic data from controls to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions linked to expression levels of recently evolved genes. In addition, we asked whether genes whose expression correlates with FTLD atrophy are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired. We found that FTLD-TDP and FTLD-tau subtypes target brain regions with overlapping and distinct gene expression correlates, highlighting many genes linked to neuromodulatory functions. FTLD atrophy-correlated genes were strongly enriched for HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes and genes with more numerous TDP-43 binding sites compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes. Overall, our findings suggest that FTLD targets brain regions that have undergone recent evolutionary specialization and provide intriguing potential leads regarding the transcriptomic basis for selective vulnerability in distinct FTLD molecular-anatomical subtypes.

INTRODUCTION: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis. METHODS: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes. RESULTS: CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function. DISCUSSION: The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID. HIGHLIGHTS: This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection.

While regular physical activity is a cornerstone of health, wellness, and vitality, the impact of endurance exercise training on molecular signaling within and across tissues remains to be delineated. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to characterize molecular networks underlying the adaptive response to exercise. Here, we describe the endurance exercise training studies undertaken by the Preclinical Animal Sites Studies component of MoTrPAC, in which we sought to develop and implement a standardized endurance exercise protocol in a large cohort of rats. To this end, Adult (6-mo) and Aged (18-mo) female (n = 151) and male (n = 143) Fischer 344 rats were subjected to progressive treadmill training (5 d/wk, ∼70%-75% VO2max) for 1, 2, 4, or 8 wk; sedentary rats were studied as the control group. A total of 18 solid tissues, as well as blood, plasma, and feces, were collected to establish a publicly accessible biorepository and for extensive omics-based analyses by MoTrPAC. Treadmill training was highly effective, with robust improvements in skeletal muscle citrate synthase activity in as little as 1-2 wk and improvements in maximum run speed and maximal oxygen uptake by 4-8 wk. For body mass and composition, notable age- and sex-dependent responses were observed. This work in mature, treadmill-trained rats represents the most comprehensive and publicly accessible tissue biorepository, to date, and provides an unprecedented resource for studying temporal-, sex-, and age-specific responses to endurance exercise training in a preclinical rat model.

BACKGROUND: Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk. METHODS: Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11-36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones. RESULTS: Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20). CONCLUSIONS: Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.

Cardiorespiratory fitness and mitochondrial oxidative capacity are associated with reduced walking speed in older adults, but their impact on walking speed in older adults with diabetes has not been clearly defined. We examined differences in cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity between older adults with and without diabetes, as well as determined their relative contribution to slower walking speed in older adults with diabetes. Participants with diabetes (n = 159) had lower cardiorespiratory fitness and mitochondrial respiration in permeabilized fiber bundles compared with those without diabetes (n = 717), following adjustments for covariates including BMI, chronic comorbid health conditions, and physical activity. Four-meter and 400-m walking speeds were slower in those with diabetes. Mitochondrial oxidative capacity alone or combined with cardiorespiratory fitness mediated ∼20-70% of the difference in walking speed between older adults with and without diabetes. Additional adjustments for BMI and comorbidities further explained the group differences in walking speed. Cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity contribute to slower walking speeds in older adults with diabetes.

Identifying immune correlates of protection is a major challenge in AIDS vaccine development. Anti-Envelope antibodies have been considered critical for protection against SIV/HIV (SHIV) acquisition. Here, we evaluated the efficacy of an SHIV vaccine against SIVmac251 challenge, where the role of antibody was excluded, as there was no cross-reactivity between SIV and SHIV envelope antibodies. After 8 low-dose intrarectal challenges with SIVmac251, 12 SHIV-vaccinated animals demonstrated efficacy, compared with 6 naive controls, suggesting protection was achieved in the absence of anti-envelope antibodies. Interestingly, CD8+ T cells (and some NK cells) were not essential for preventing viral acquisition, as none of the CD8-depleted macaques were infected by SIVmac251 challenges. Initial investigation of protective innate immunity revealed that protected animals had elevated pathways related to platelet aggregation/activation and reduced pathways related to interferon and responses to virus. Moreover, higher expression of platelet factor 4 on circulating platelet-leukocyte aggregates was associated with reduced viral acquisition. Our data highlighted the importance of innate immunity, identified mechanisms, and may provide opportunities for novel HIV vaccines or therapeutic strategy development.

Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood1-3. Here, the Molecular Transducers of Physical Activity Consortium4 profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue-specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository ( https://motrpac-data.org/ ).

BACKGROUND AND OBJECTIVES: Cavum septum pellucidum (CSP) is a common but nonspecific MRI finding in individuals with prior head trauma. The type and extent of head trauma related to CSP, CSP features specific to head trauma, and the impact of brain atrophy on CSP are unknown. We evaluated CSP cross-sectionally and longitudinally in healthy and clinically impaired older adults who underwent detailed lifetime head trauma characterization. METHODS: This is an observational cohort study of University of California, San Francisco Memory and Aging Center participants (healthy controls [HCs], those with Alzheimer disease or related dementias [ADRDs], subset with traumatic encephalopathy syndrome [TES]). We characterized traumatic brain injury (TBI) and repetitive head impacts (RHI) through contact/collision sports. Study groups were no RHI/TBI, prior TBI only, prior RHI only, and prior RHI + TBI. We additionally looked within TBI (1, 2, or 3+) and RHI (1-4, 5-10, and 11+ years). All underwent baseline MRI, and 67% completed a second MRI (median follow-up = 5.4 years). CSP measures included grade (0-4) and length (millimeters). Groups were compared on likelihood of CSP (logistic regression, odds ratios [ORs]) and whether CSP length discriminated groups (area under the curve [AUC]). RESULTS: Our sample included 266 participants (N = 160 HCs, N = 106 with ADRD or TES; age 66.8 ± 8.2 years, 45.3% female). Overall, 123 (49.8%) participants had no RHI/TBI, 52 (21.1%) had TBI only, 41 (16.6%) had RHI only, 31 (12.6%) had RHI + TBI, and 20 were classified as those with TES (7.5%). Compared with no RHI/TBI, RHI + TBI (OR 3.11 [1.23-7.88]) and TES (OR 11.6 [2.46-54.8]) had greater odds of CSP. Approximately 5-10 years (OR 2.96 [1.13-7.77]) and 11+ years of RHI (OR 3.14 [1.06-9.31]) had higher odds of CSP. CSP length modestly discriminated participants with 5-10 years (AUC 0.63 [0.51-0.75]) and 11+ years of prior RHI (AUC 0.69 [0.55-0.84]) from no RHI/TBI (cut point = 6 mm). Strongest effects were noted in analyses of American football participation. Longitudinally, CSP grade was unchanged in 165 (91.7%), and length was unchanged in 171 (95.5%) participants. DISCUSSION: Among older adults with and without neurodegenerative disease, risk of CSP is driven more by duration (years) of RHI, especially American football, than number of TBI. CSP length (≥6 mm) is relatively specific to individuals who have had substantial prior RHI. Neurodegenerative disease and progressive atrophy do not clearly influence development or worsening of CSP.

BACKGROUND: Phenotypic frailty syndrome identifies older adults at greater risk for adverse health outcomes. Despite the critical role of mitochondria in maintaining cellular function, including energy production, the associations between muscle mitochondrial energetics and frailty have not been widely explored in a large, well-phenotyped, older population. METHODS: The Study of Muscle, Mobility and Aging (SOMMA) assessed muscle energetics in older adults (N = 879, mean age = 76.3 years, 59.2% women). 31Phosporous magnetic resonance spectroscopy measured maximal production of adenosine triphosphate (ATPmax) in vivo, while ex vivo high-resolution respirometry of permeabilized muscle fibers from the vastus lateralis measured maximal oxygen consumption supported by fatty acids and complex I- and II-linked carbohydrates (e.g., Max OXPHOSCI+CII). Five frailty criteria, shrinking, weakness, exhaustion, slowness, and low activity, were used to classify participants as robust (0, N = 397), intermediate (1-2, N = 410), or frail (≥ 3, N = 66). We estimated the proportional odds ratio (POR) for greater frailty, adjusted for multiple potential confounders. RESULTS: One-SD decrements of most respirometry measures (e.g., Max OXPHOSCI+CII, adjusted POR = 1.5, 95%CI [1.2,1.8], p = 0.0001) were significantly associated with greater frailty classification. The associations of ATPmax with frailty were weaker than those between Max OXPHOSCI+CII and frailty. Muscle energetics was most strongly associated with slowness and low physical activity components. CONCLUSIONS: Our data suggest that deficits in muscle mitochondrial energetics may be a biological driver of frailty in older adults. On the other hand, we did observe differential relationships between measures of muscle mitochondrial energetics and the individual components of frailty.

Social stress experienced in childhood is associated with adverse health later in life. Mitochondrial function has been implicated as a mechanism for how stressful life events get under the skin to influence physical well-being. Using data from the Study of Muscle, Mobility, and Aging (n = 879, 59% women), linear models examined whether adverse childhood events (i.e., physical abuse) were associated with two measures of skeletal muscle mitochondrial energetics in older adults: (i) maximal adenosine triphosphate production (ATPmax) and (ii) maximal state 3 respiration (Max OXPHOS). Forty-five percent of the sample reported experiencing one or more adverse childhood events. After adjustment, each additional event was associated with -0.08 SD (95% confidence interval = -0.13, -0.02) lower ATPmax. No association was observed with Max OXPHOS. Adverse childhood events are associated with lower ATP production in later life. Findings indicate that mitochondrial function may be a mechanism for understanding how early social stress influences health in later life.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

BackgroundLiver fibrosis is caused by chronic toxic or cholestatic liver injury. Fibrosis results from the recruitment of myeloid cells into the injured liver, the release of inflammatory and fibrogenic cytokines, and the activation of myofibroblasts, which secrete extracellular matrix, mostly collagen type I. Hepatic myofibroblasts originate from liver-resident mesenchymal cells, including HSCs and bone marrow-derived CD45+ collagen type I+ expressing fibrocytes. Recombinant human serum amyloid P (hSAP), a natural inhibitor of fibrocyte activation into myofibroblasts, was shown to ameliorate experimental renal, lung, skin, and cardiac fibrosis. We investigated if hSAP can ameliorate the development of liver fibrosis of different etiologies.MethodsReporter Collagen-α(1)I-GFP mice were subjected to cholestatic liver injury (by ligation of the common bile duct) or toxic liver injury (by carbon tetrachloride administration) and treated prophylactically or therapeutically with hSAP (12.5 μg/g). Primary cultures of mouse fibrocytes and HSCs were stimulated to activate with or without incubation with hSAP.ResultsWe demonstrate that treatment with hSAP suppressed hepatic fibrosis by ≈50% through dual mechanisms. hSAP prevented the recruitment of fibrocytes into the injured liver and their differentiation into myofibroblasts. Remarkably, hSAP also inhibited the activation of HSCs into myofibroblasts.ConclusionsSince HSCs serve as a major source of collagen type I-producing myofibroblasts and fibrocytes stimulate fibrosis, hSAP may become part of the therapy of liver fibrosis of different etiologies.

BackgroundTraumatic brain injury (TBI) and repetitive head impacts (RHI) have been linked to increased risk for multiple types of neurodegenerative disease, higher dementia risk, and earlier age of dementia symptom onset, suggesting transdiagnostic implications for later-life brain health. Frontotemporal dementia (FTD) and primary progressive aphasia (PPA) represent a spectrum of clinical phenotypes that are neuropathologically diverse. FTD/PPA diagnoses bring unique challenges due to complex cognitive and behavioral symptoms that disproportionately present as an early-onset dementia (before age 65). We performed a detailed characterization of lifetime head trauma exposure in individuals with FTD and PPA compared to healthy controls to examine frequency of lifetime TBI and RHI and associated clinical implications.MethodsWe studied 132 FTD/PPA (age 68.9 ± 8.1, 65% male) and 132 sex-matched healthy controls (HC; age 73.4 ± 7.6). We compared rates of prior TBI and RHI (contact/collision sports) between FTD/PPA and HC (chi-square, logistic regression, analysis of variance). Within FTD/PPA, we evaluated associations with age of symptom onset (analysis of variance). Within behavioral variant FTD, we evaluated associations with cognitive function and neuropsychiatric symptoms (linear regression controlling for age, sex, and years of education).ResultsYears of participation were greater in FTD/PPA than HC for any contact/collision sport (8.5 ± 6.7yrs vs. 5.3 ± 4.5yrs, p = .008) and for American football (6.2yrs ± 4.3yrs vs. 3.1 ± 2.4yrs; p = .003). Within FTD/PPA, there were dose-dependent associations with earlier age of symptom onset for TBI (0 TBI: 62.1 ± 8.1, 1 TBI: 59.9 ± 6.9, 2 + TBI: 57.3 ± 8.4; p = .03) and years of American football (0yrs: 62.2 ± 8.7, 1-4yrs: 59.7 ± 7.0, 5 + yrs: 55.9 ± 6.3; p = .009). Within bvFTD, those who played American football had worse memory (z-score: -2.4 ± 1.2 vs. -1.4 ± 1.6, p = .02, d = 1.1).ConclusionsLifetime head trauma may represent a preventable environmental risk factor for FTD/PPA. Dose-dependent exposure to TBI or RHI influences FTD/PPA symptom onset and memory function in bvFTD. Clinico-pathological studies are needed to better understand the neuropathological correlates linking RHI or TBI to FTD/PPA onset and symptoms.

Chronic kidney disease (CKD) impacts about 1 in 7 adults in the United States, but African Americans (AAs) carry a disproportionately higher burden of disease. Epigenetic modifications, such as DNA methylation at cytosine-phosphate-guanine (CpG) sites, have been linked to kidney function and may have clinical utility in predicting the risk of CKD. Given the dynamic relationship between the epigenome, environment, and disease, AAs may be especially sensitive to environment-driven methylation alterations. Moreover, risk models incorporating CpG methylation have been shown to predict disease across multiple racial groups. In this study, we developed a methylation risk score (MRS) for CKD in cohorts of AAs. We selected nine CpG sites that were previously reported to be associated with estimated glomerular filtration rate (eGFR) in epigenome-wide association studies to construct a MRS in the Hypertension Genetic Epidemiology Network (HyperGEN). In logistic mixed models, the MRS was significantly associated with prevalent CKD and was robust to multiple sensitivity analyses, including CKD risk factors. There was modest replication in validation cohorts. In summary, we demonstrated that an eGFR-based CpG score is an independent predictor of prevalent CKD, suggesting that MRS should be further investigated for clinical utility in evaluating CKD risk and progression.

BackgroundFrontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged

IntroductionWe used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early-onset Alzheimer's disease (EOAD).MethodsWe included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non-Alzheimer's disease (EOnonAD) participants from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel-wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden.ResultsEOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non-carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non-carriers also had greater gray matter atrophy than female ε4 carriers.DiscussionThe effects of sex and APOE ε4 must be considered when studying these populations.HighlightsNovel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOE ε4) carrier status on neuroimaging biomarkers among early-onset Alzheimer's disease (EOAD), early-onset non-AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts.

BackgroundThe pathophysiology of delirium is incompletely understood, including what molecular pathways are involved in brain vulnerability to delirium. This study examined whether preoperative plasma neurodegeneration markers were elevated in patients who subsequently developed postoperative delirium through a retrospective case-control study.MethodsInclusion criteria were patients of 65 yr of age or older, undergoing elective noncardiac surgery with a hospital stay of 2 days or more. Concentrations of preoperative plasma P-Tau181, neurofilament light chain, amyloid β1-42 (Aβ42), and glial fibrillary acidic protein were measured with a digital immunoassay platform. The primary outcome was postoperative delirium measured by the Confusion Assessment Method. The study included propensity score matching by age and sex with nearest neighbor, such that each patient in the delirium group was matched by age and sex with a patient in the no-delirium group.ResultsThe initial cohort consists of 189 patients with no delirium and 102 patients who developed postoperative delirium. Of 291 patients aged 72.5 ± 5.8 yr, 50.5% were women, and 102 (35%) developed postoperative delirium. The final cohort in the analysis consisted of a no-delirium group (n = 102) and a delirium group (n = 102) matched by age and sex using the propensity score method. Of the four biomarkers assayed, the median value for neurofilament light chain was 32.05 pg/ml for the delirium group versus 23.7 pg/ml in the no-delirium group. The distribution of biomarker values significantly differed between the delirium and no-delirium groups (P = 0.02 by the Kolmogorov-Smirnov test) with the largest cumulative probability difference appearing at the biomarker value of 32.05 pg/ml.ConclusionsThese results suggest that patients who subsequently developed delirium are more likely to be experiencing clinically silent neurodegenerative changes before surgery, reflected by changes in plasma neurofilament light chain biomarker concentrations, which may identify individuals with a preoperative vulnerability to subsequent cognitive decline.Editor’s perspective

PURPOSE: The proPSMA trial at ten Australian centers demonstrated increased sensitivity and specificity for PSMA PET/CT compared to conventional imaging regarding metastatic status in primary high-risk prostate cancer patients. A cost-effectiveness analysis showed benefits of PSMA PET/CT over conventional imaging for the Australian setting. However, comparable data for other countries are lacking. Therefore, we aimed to verify the cost-effectiveness of PSMA PET/CT in several European countries as well as the USA. METHODS: Clinical data on diagnostic accuracy were derived from the proPSMA trial. Costs for PSMA PET/CT and conventional imaging were taken from reimbursements of national health systems and individual billing information of selected centers in Belgium, Germany, Italy, the Netherlands, and the USA. For comparability, scan duration and the decision tree of the analysis were adopted from the Australian cost-effectiveness study. RESULTS: In contrast to the Australian setting, PSMA PET/CT was primarily associated with increased costs in the studied centers in Europe and the USA. Mainly, the scan duration had an impact on the cost-effectiveness. However, costs for an accurate diagnosis using PSMA PET/CT seemed reasonably low compared to the potential consequential costs of an inaccurate diagnosis. CONCLUSION: We assume that the use of PSMA PET/CT is appropriate from a health economic perspective, but this will need to be verified by a prospective evaluation of patients at initial diagnosis.

Patients with atypical anorexia nervosa (AAN) or anorexia nervosa (AN) with premorbid history of higher weight (PHW; median BMI ≥ 85th %ile) may report greater eating disorder (ED) pathology, anxiety, and depression, than patients with premorbid history of lower weight (PLW; mBMI  .05). Adolescents with PHW (vs. PLW) were more likely to be diagnosed with AAN (67.9 %, p

IntroductionWe tested sex-dependent associations of variation in the SNAP-25 gene, which encodes a presynaptic protein involved in hippocampal plasticity and memory, on cognitive and Alzheimer's disease (AD) neuroimaging outcomes in clinically normal adults.MethodsParticipants were genotyped for SNAP-25 rs1051312 (T > C; SNAP-25 expression: C-allele > T/T). In a discovery cohort (N = 311), we tested the sex by SNAP-25 variant interaction on cognition, Aβ-PET positivity, and temporal lobe volumes. Cognitive models were replicated in an independent cohort (N = 82).ResultsIn the discovery cohort, C-allele carriers exhibited better verbal memory and language, lower Aβ-PET positivity rates, and larger temporal volumes than T/T homozygotes among females, but not males. Larger temporal volumes related to better verbal memory only in C-carrier females. The female-specific C-allele verbal memory advantage was evidenced in the replication cohort.ConclusionsIn females, genetic variation in SNAP-25 is associated with resistance to amyloid plaque formation and may support verbal memory through fortification of temporal lobe architecture.HighlightsThe SNAP-25 rs1051312 (T > C) C-allele results in higher basal SNAP-25 expression. C-allele carriers had better verbal memory in clinically normal women, but not men. Female C-carriers had higher temporal lobe volumes, which predicted verbal memory. Female C-carriers also exhibited the lowest rates of amyloid-beta PET positivity. The SNAP-25 gene may influence female-specific resistance to Alzheimer's disease (AD).

ObjectiveChronic stress adversely affects cognition, in part due to stress-induced inflammation. Rodent models suggest females are more resilient against stress-related cognitive dysfunction than males; however, few studies have examined this in humans. We examined sex differences in the relationship between perceived stress, cognitive functioning, and peripheral inflammation over time among cognitively normal older adults.DesignLongitudinal observational study.SettingUniversity research center.Participants274 community-dwelling older adults (baseline age: M=70.7, SD=7.2; 58% women; Clinical Dementia Rating=0) who completed at least two study visits.MeasurementsNeurocognitive functioning and perceived stress (Perceived Stress Scale [PSS]) were assessed at each visit. Plasma was analyzed for interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in a subset of 147 participants. Linear mixed effects models examined the interaction between average PSS (i.e., averaged within persons across visits), sex, and time on cognitive domains and on inflammatory markers.ResultsThe interaction between stress, sex, and time predicted executive functioning (β = 0.26, SE = 0.10, p = 0.01) such that higher average PSS related to steeper declines in men, but not in women. Among the 147 participants with inflammatory data, higher average PSS was associated with steeper increases in IL-6 over time in men, but not in women.ConclusionConsistent with animal models, results showed older men were more vulnerable to negative effects of stress on cognitive aging, with domain-specific declines in executive function. Findings also suggest systemic immunological mechanisms may underlie increased risk for cognitive decline in men with higher levels of stress. Future work is needed to examine the potential efficacy of person-specific stress interventions.

To address claims of human exceptionalism, we determine where humans fit within the greater mammalian distribution of reproductive inequality. We show that humans exhibit lower reproductive skew (i.e., inequality in the number of surviving offspring) among males and smaller sex differences in reproductive skew than most other mammals, while nevertheless falling within the mammalian range. Additionally, female reproductive skew is higher in polygynous human populations than in polygynous nonhumans mammals on average. This patterning of skew can be attributed in part to the prevalence of monogamy in humans compared to the predominance of polygyny in nonhuman mammals, to the limited degree of polygyny in the human societies that practice it, and to the importance of unequally held rival resources to women's fitness. The muted reproductive inequality observed in humans appears to be linked to several unusual characteristics of our species-including high levels of cooperation among males, high dependence on unequally held rival resources, complementarities between maternal and paternal investment, as well as social and legal institutions that enforce monogamous norms.

ImportancePlasma phosphorylated tau217 (p-tau217), a biomarker of Alzheimer disease (AD), is of special interest in corticobasal syndrome (CBS) because autopsy studies have revealed AD is the driving neuropathology in up to 40% of cases. This differentiates CBS from other 4-repeat tauopathy (4RT)-associated syndromes, such as progressive supranuclear palsy Richardson syndrome (PSP-RS) and nonfluent primary progressive aphasia (nfvPPA), where underlying frontotemporal lobar degeneration (FTLD) is typically the primary neuropathology.ObjectiveTo validate plasma p-tau217 against positron emission tomography (PET) in 4RT-associated syndromes, especially CBS.Design, setting, and participantsThis multicohort study with 6, 12, and 24-month follow-up recruited adult participants between January 2011 and September 2020 from 8 tertiary care centers in the 4RT Neuroimaging Initiative (4RTNI). All participants with CBS (n = 113), PSP-RS (n = 121), and nfvPPA (n = 39) were included; other diagnoses were excluded due to rarity (n = 29). Individuals with PET-confirmed AD (n = 54) and PET-negative cognitively normal control individuals (n = 59) were evaluated at University of California San Francisco. Operators were blinded to the cohort.Main outcome and measuresPlasma p-tau217, measured by Meso Scale Discovery electrochemiluminescence, was validated against amyloid-β (Aβ) and flortaucipir (FTP) PET. Imaging analyses used voxel-based morphometry and bayesian linear mixed-effects modeling. Clinical biomarker associations were evaluated using longitudinal mixed-effect modeling.ResultsOf 386 participants, 199 (52%) were female, and the mean (SD) age was 68 (8) years. Plasma p-tau217 was elevated in patients with CBS with positive Aβ PET results (mean [SD], 0.57 [0.43] pg/mL) or FTP PET (mean [SD], 0.75 [0.30] pg/mL) to concentrations comparable to control individuals with AD (mean [SD], 0.72 [0.37]), whereas PSP-RS and nfvPPA showed no increase relative to control. Within CBS, p-tau217 had excellent diagnostic performance with area under the receiver operating characteristic curve (AUC) for Aβ PET of 0.87 (95% CI, 0.76-0.98; P

Attaching semantic meaning to sensory information received from both inside and outside our bodies is a fundamental function of the human brain. The theory of Controlled Semantic Cognition (CSC) proposes that the formation of semantic knowledge relies on connections between spatially distributed modality-specific spoke-nodes, and a modality-general hub in the anterior temporal lobes (ATLs). This theory can also be applied to social semantic knowledge, though certain domain-specific spoke-nodes may make a disproportionate contribution to the understanding of social concepts. The ATLs have strong connections with spoke-node structures such as the subgenual ACC (sgACC) and the orbitofrontal cortex (OFC) that play an important role in predicting the hedonic value of stimuli. We hypothesized that in addition to the ATL semantic hub, a social semantic task would also require input from hedonic evaluation structures. We used voxel based morphometry (VBM) to examine structural brain-behavior relationships in 152 patients with neurodegeneration (Alzheimer's disease [N = 12], corticobasal syndrome (N = 18], progressive supranuclear palsy [N = 13], behavioral variant frontotemporal dementia [N = 56], and primary progressive aphasia (PPA) [N = 53]) using the Social Interaction Vocabulary Task (SIVT). This task measures the ability to correctly match a social term (e.g. "gossiping") with a visual depiction of that social interaction. As predicted, VBM showed that worse SIVT scores corresponded with volume loss in bilateral ATL semantic hub regions, but also in the sgACC, OFC, caudate and putamen (pFWE

We tested whether aspects of the childhood/adolescent home environment mediate genetic risk for alcohol problems within families across generations. Parental relationship discord and parental divorce were the focal environments examined. The sample included participants of European ancestry (N = 4806, 51% female) and African ancestry (N = 1960, 52% female) from the high-risk Collaborative Study on the Genetics of Alcoholism. Alcohol outcomes in the child generation included lifetime criterion counts for DSM-5 Alcohol Use Disorder (AUD), lifetime maximum drinks in 24 h, age at initiation of regular drinking, and age at first alcohol intoxication. Predictors in the parent generation included relationship discord, divorce, alcohol measures parallel to those in the child generation, and polygenic scores for alcohol problems. Parental polygenic scores were partitioned into alleles that were transmitted and non-transmitted to the child. The results from structural equation models were consistent with genetic nurture effects in European ancestry families. Exposure to parental relationship discord and parental divorce mediated, in part, the transmission of genetic risk for alcohol problems from parents to children to predict earlier ages regular drinking (βindirect = -0.018 [-0.026, -0.011]) and intoxication (βindirect = -0.015 [-0.023, -0.008]), greater lifetime maximum drinks (βindirect = 0.006 [0.002, 0.01]) and more lifetime AUD criteria (βindirect = 0.011 [0.006, 0.016]). In contrast, there was no evidence that parental alleles had indirect effects on offspring alcohol outcomes via parental relationship discord or divorce in the smaller number of families of African ancestry. In conclusion, parents transmit genetic risk for alcohol problems to their children not only directly, but also indirectly via genetically influenced aspects of the home environment. Further investigation of genetic nurture in non-European samples is needed.

Hexanucleotide repeat expansion (HRE) within C9orf72 is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread derepression of transposable elements (TEs) in the brain in several neurodegenerative diseases, including C9orf72 HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheral C9orf72 expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used FreeSurfer software to assess the effects of C9orf72 HRE and clinical diagnosis (n = 78 individuals, male and female) on atrophy of thalamic nuclei. We also generated a novel, human, whole-blood RNA-sequencing dataset to determine the relationships among peripheral C9orf72 expression, TE activation, thalamic atrophy, and clinical severity (n = 114 individuals, male and female). We confirmed global thalamic atrophy and reduced C9orf72 expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed that C9orf72 expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 element L1HS L1HS levels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from human HRE carriers revealed atrophy of specific thalamic nuclei, demonstrated that C9orf72 levels relate to clinical severity, and identified marked derepression of TEs, including L1HS, which predicted atrophy of FTD-relevant thalamic nuclei.SIGNIFICANCE STATEMENT Pathogenic repeat expansion in C9orf72 is the most frequent genetic cause of FTD and amyotrophic lateral sclerosis (ALS; C9-FTD/ALS). The clinical, neuroimaging, and pathologic features of C9-FTD/ALS are well characterized, whereas the intersections of transcriptomic dysregulation and brain structure remain largely unexplored. Herein, we used a novel radiogenomic approach to examine the relationship between peripheral blood transcriptomics and thalamic atrophy, a neuroimaging feature disproportionately impacted in C9-FTD/ALS. We confirmed reduction of C9orf72 in blood and found broad dysregulation of transposable elements-genetic elements typically repressed in the human genome-in symptomatic C9orf72 expansion carriers, which associated with atrophy of thalamic nuclei relevant to FTD. C9orf72 expression was also associated with clinical severity, suggesting that peripheral C9orf72 levels capture disease-relevant information.

BackgroundParents impact their offspring's brain development, neurocognitive function, risk, and resilience for alcohol use disorder (AUD) via both genetic and socio-environmental factors. Individuals with AUD and their unaffected children manifest low parietal P3 amplitude and low frontal theta (FT) power, reflecting heritable neurocognitive deficits associated with AUD. Likewise, children who experience poor parenting tend to have atypical brain development and greater rates of alcohol problems. Conversely, positive parenting can be protective and critical for normative development of self-regulation, neurocognitive functioning and the neurobiological systems subserving them. Yet, the role of positive parenting in resiliency toward AUD is understudied and its association with neurocognitive functioning and behavioral vulnerability to AUD among high-risk offspring is less known. Using data from the Collaborative Study on the Genetics of Alcoholism prospective cohort (N = 1256, mean age [SD] = 19.25 [1.88]), we investigated the associations of closeness with mother and father during adolescence with offspring P3 amplitude, FT power, and binge drinking among high-risk offspring.MethodsSelf-reported closeness with mother and father between ages 12 and 17 and binge drinking were assessed using the Semi-Structured Assessment for the Genetics of Alcoholism. P3 amplitude and FT power were assessed in response to target stimuli using a Visual Oddball Task.ResultsMultivariate multiple regression analyses showed that closeness with father was associated with larger P3 amplitude (p = 0.002) and higher FT power (p = 0.01). Closeness with mother was associated with less binge drinking (p = 0.003). Among male offspring, closeness with father was associated with larger P3 amplitude, but among female offspring, closeness with mother was associated with less binge drinking. These associations remained statistically significant with father's and mothers' AUD symptoms, socioeconomic status, and offspring impulsivity in the model.ConclusionsAmong high-risk offspring, closeness with parents during adolescence may promote resilience for developing AUD and related neurocognitive deficits albeit with important sex differences.

PurposeCaregivers play a pivotal role in the success of family-based treatment (FBT) for anorexia nervosa (AN). Caregiver burden is frequently demonstrated in eating disorders (EDs) and may impact FBT outcomes. This study examined factors associated with caregiver burden before starting FBT and whether pre-treatment caregiver burden was associated with weight gain during FBT.MethodsParticipants included 114 adolescents with AN or atypical AN (mean age = 15.6 years, SD = 1.4) and a primary caregiver (87.6% mothers) who received FBT in the United States. Before starting treatment, participants completed self-report measures of caregiver burden (via the Eating Disorder Symptom Impact Scale), caregiver anxiety, caregiver depression, and ED symptoms. Clinical characteristics and percentage of target goal weight (%TGW) at FBT session 1 and 3 and 6 months after starting treatment were obtained via retrospective chart review. Hierarchical regressions examined predictors of caregiver burden before FBT initiation. Associations between pre-treatment caregiver burden and %TGW gain at 3 and 6 months after starting FBT were assessed with hierarchical regressions.ResultsCaregiver anxiety (p

Early-onset (age < 65) Alzheimer's disease is associated with greater non-amnestic cognitive symptoms and neuropathological burden than late-onset disease. It is not fully understood whether these groups also differ in the associations between molecular pathology, neurodegeneration and cognitive performance. We studied amyloid-positive patients with early-onset (n = 60, mean age 58 ± 4, MMSE 21 ± 6, 58% female) and late-onset (n = 53, mean age 74 ± 6, MMSE 23 ± 5, 45% female) Alzheimer's disease who underwent neurological evaluation, neuropsychological testing, 11C-Pittsburgh compound B PET (amyloid-PET) and 18F-flortaucipir PET (tau-PET). 18F-fluorodeoxyglucose PET (brain glucose metabolism PET) was also available in 74% (n = 84) of participants. Composite scores for episodic memory, semantic memory, language, executive function and visuospatial domains were calculated based on cognitively unimpaired controls. Voxel-wise regressions evaluated correlations between PET biomarkers and cognitive scores and early-onset versus late-onset differences were tested with a PET × Age group interaction. Mediation analyses estimated direct and indirect (18F-fluorodeoxyglucose mediated) local associations between 18F-flortaucipir binding and cognitive scores in domain-specific regions of interest. We found that early-onset patients had higher 18F-flortaucipir binding in parietal, lateral temporal and lateral frontal cortex; more severe 18F-fluorodeoxyglucose hypometabolism in the precuneus and angular gyrus; and greater 11C-Pittsburgh compound B binding in occipital regions compared to late-onset patients. In our primary analyses, PET-cognition correlations did not meaningfully differ between age groups.18F-flortaucipir and 18F-fluorodeoxyglucose, but not 11C-Pittsburgh compound B, were significantly associated with cognition in expected domain-specific patterns in both age groups (e.g. left perisylvian/language, frontal/executive, occipital/visuospatial). 18F-fluorodeoxyglucose mediated the relationship between 18F-flortaucipir and cognition in both age groups across all domains except episodic memory in late-onset patients. Additional direct effects of 18F-flortaucipir were observed for executive function in all age groups, language in early-onset Alzheimer's disease and in the total sample and visuospatial function in the total sample. In conclusion, tau and neurodegeneration, but not amyloid, were similarly associated with cognition in both early and late-onset Alzheimer's disease. Tau had an association with cognition independent of neurodegeneration in language, executive and visuospatial functions in the total sample. Our findings support tau PET as a biomarker that captures both the clinical severity and molecular pathology specific to Alzheimer's disease across the broad spectrum of ages and clinical phenotypes in Alzheimer's disease.

Converging lines of inquiry from across the social and biological sciences target the adult sex ratio (ASR; the proportion of males in the adult population) as a fundamental population-level determinant of behavior. The ASR, which indicates the relative number of potential mates to competitors in a population, frames the selective arena for competition, mate choice, and social interactions. Here we review a growing literature, focusing on methodological developments that sharpen knowledge of the demographic variables underlying ASR variation, experiments that enhance understanding of the consequences of ASR imbalance across societies, and phylogenetic analyses that provide novel insights into social evolution. We additionally highlight areas where research advances are expected to make accelerating contributions across the social sciences, evolutionary biology, and biodiversity conservation.

Traumatic encephalopathy syndrome (TES) criteria were developed to aid diagnosis of chronic traumatic encephalopathy (CTE) pathology during life. Interpreting clinical and biomarker findings in patients with TES during life necessitates autopsy-based determination of the neuropathological profile. We report a clinicopathological series of nine patients with previous repetitive head impacts (RHI) classified retrospectively using the recent TES research framework (100% male and white/Caucasian, age at death 49-84) who completed antemortem neuropsychological evaluations, T1-weighted magnetic resonance imaging, diffusion tensor imaging (n = 6), (18)F-fluorodeoxyglucose-positron emission tomography (n = 5), and plasma measurement of neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and total tau (n = 8). Autopsies were performed on all patients. Cognitively, low test scores and longitudinal decline were relatively consistent for memory and executive function. Medial temporal lobe atrophy was observed in all nine patients. Poor white matter integrity was consistently found in the fornix. Glucose hypometabolism was most common in the medial temporal lobe and thalamus. Most patients had elevated plasma GFAP, NfL, and total tau at their initial visit and a subset showed longitudinally increasing concentrations. Neuropathologically, five of the nine patients had CTE pathology (n = 4 "High CTE"/McKee Stage III-IV, n = 1 "Low CTE"/McKee Stage I). Primary neuropathological diagnoses (i.e., the disease considered most responsible for observed symptoms) were frontotemporal lobar degeneration (n = 2 FTLD-TDP, n = 1 FTLD-tau), Alzheimer disease (n = 3), CTE (n = 2), and primary age-related tauopathy (n = 1). In addition, hippocampal sclerosis was a common neuropathological comorbidity (n = 5) and associated with limbic-predominant TDP-43 proteinopathy (n = 4) or FTLD-TDP (n = 1). Memory and executive function decline, limbic system brain changes (atrophy, decreased white matter integrity, hypometabolism), and plasma biomarker alterations are common in RHI and TES but may reflect multiple neuropathologies. In particular, the neuropathological differential for patients with RHI or TES presenting with medial temporal atrophy and memory loss should include limbic TDP-43. Researchers and clinicians should be cautious in attributing cognitive, neuroimaging, or other biomarker changes solely to CTE tau pathology based on previous RHI or a TES diagnosis alone.

ObjectiveTo examine associations between alcohol use disorder (AUD), its psychiatric comorbidities, and their interactions, with marital outcomes in a diverse high-risk, genetically informative sample.MethodParticipants included European ancestry (EA; n = 4,045) and African ancestry (AA; n = 1,550) individuals from the multigenerational Collaborative Study on the Genetics of Alcoholism (COGA) sample (56% female, Mage ∼ 41 years). Outcomes were lifetime marriage and divorce. Predictors included lifetime AUD, an alcohol problems polygenic score (PRS), and AUD comorbidities, including conduct or antisocial personality disorder (ASP), cannabis dependence/abuse (CAN), frequent tobacco use (TOB), and major depressive disorder (MDD). Mixed effect Cox models and generalized linear mixed effects models were fit.ResultsAmong EA participants, those with AUD and CAN were less likely to marry (hazard ratios [HRs] 0.70-0.83, ps < 0.01). Among AA participants, those with AUD and TOB were less likely to marry (HRs 0.66-0.82, ps < 0.05) and those with MDD were more likely to marry (HR = 1.34, ps < 0.01). Among EA participants, AUD, CAN, TOB, and MDD were associated with higher odds of divorce (odds ratios [ORs] 1.59-2.21, ps < 0.01). Among AA participants, no predictors were significantly associated with divorce. Significant random effects indicated genetic and environmental influences on marriage, but only environmental factors on divorce.ConclusionsIn a high-risk sample, AUD was associated with reduced likelihood of marriage in EA and AA individuals and increased risk of divorce in EA individuals. These associations were largely independent of comorbidities. Genetic and environmental background factors contributed to marriage, while only environmental background factors contributed to divorce. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

BackgroundSmoking starts in early adulthood and persists throughout the life course, but the association between these trajectories and midlife cognition remains unclear.ObjectiveDetermine the association between early to midlife smoking trajectories and midlife cognition.DesignProspective cohort study.ParticipantsParticipants were 3364 adults (mean age = 50.1 ± 3.6, 56% female, 46% Black) from the Coronary Artery Risk Development in Young Adults (CARDIA) study: 1638 ever smokers and 1726 never smokers.Main measuresSmoking trajectories were identified in latent class analysis among 1638 ever smokers using smoking measures every 2-5 years from baseline (age 18-30 in 1985-1986) through year 25 (2010-2011). Poor cognition was based on cognitive domain scores ≥ 1 SD below the mean on tests of processing speed (Digit Symbol Substitution Test), executive function (Stroop), and memory (Rey Auditory Verbal Learning Test) at year 25.ResultsFive smoking trajectories emerged over 25 years: quitters (19%), and minimal stable (40%), moderate stable (20%), heavy stable (15%), and heavy declining smokers (5%). Heavy stable smokers showed poor cognition on all 3 domains compared to never smoking (processing speed AOR = 2.22 95% CI 1.53-3.22; executive function AOR = 1.58 95% CI 1.05-2.36; memory AOR = 1.48 95% CI 1.05-2.10). Compared to never smoking, both heavy declining (AOR = 1.95 95% CI 1.06-3.68) and moderate stable smokers (AOR = 1.56 95% CI 1.11-2.19) exhibited slower processing speed, and heavy declining smokers additionally had poor executive function. For minimal stable smokers (processing speed AOR = 1.12 95% CI 0.85-1.51; executive function AOR = 0.97 95% CI 0.71-1.31; memory AOR = 1.21 95% CI 0.94-1.55) and quitters (processing speed AOR = 0.96 95% CI 0.63-1.48; executive function AOR = 0.98 95% CI 0.63-1.52; memory AOR = 0.97 95% CI 0.67-1.39), no association was observed.ConclusionsThe association between early to midlife smoking trajectories and midlife cognition was dose-dependent. Results underscore the cognitive health risk of moderate and heavy smoking and the potential benefits of quitting on cognition, even in midlife.

ObjectivesThe relationship between wisdom and fluid intelligence (Gf) is poorly understood, particularly in older adults. We empirically tested the magnitude of the correlation between wisdom and Gf to help determine the extent of overlap between these two constructs.DesignCross-sectional study with preregistered hypotheses and well-powered analytic plan (https://osf.io/h3pjx).SettingMemory and Aging Center at the University of California San Francisco, located in the USA.Participants141 healthy older adults (mean age = 76 years; 56% female).MeasurementsWisdom was quantified using a well-validated self-report-based scale (San Diego Wisdom Scale or SD-WISE). Gf was assessed via composite measures of processing speed (Gf-PS) and executive functioning (Gf-EF). The relationships of SD-WISE scores to Gf-PS and Gf-EF were tested in bivariate correlational analyses and multiple regression models adjusted for demographics (age, sex, and education). Exploratory analyses evaluated the relationships between SD-WISE and age, episodic memory performance, and dorsolateral and ventromedial prefrontal cortical volumes on magnetic resonance imaging.ResultsWisdom showed a small, positive association with Gf-EF (r = 0.181 [95% CI 0.016, 0.336], p = .031), which was reduced to nonsignificance upon controlling for demographics, and no association with Gf-PS (r = 0.019 [95% CI -0.179, 0.216], p = .854). Wisdom demonstrated a small, negative correlation with age (r = -0.197 [95% CI -0.351, -0.033], p = .019), but was not significantly related to episodic memory or prefrontal volumes.ConclusionsOur findings indicate that most of the variance in wisdom (>95%) is unaccounted for by Gf. The independence of wisdom from cognitive functions that reliably show age-associated declines suggests that it may hold unique potential to bolster decision-making, interpersonal functioning, and other everyday activities in older adults.

Our objective was to examine the construct validity of the Brief Test of Adult Cognition by Telephone (BTACT) and its relationship to traumatic brain injury (TBI) of differing severities. Data were analyzed on 1422 patients with TBI and 170 orthopedic trauma controls (OTC) from the multi-center Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. Participants were assessed at 6 months post-injury with the BTACT and an in-person neuropsychological battery. We examined the BTACT's factor structure, factorial group invariance, convergent and discriminant validity, and relationship to TBI and TBI severity. Confirmatory factor analysis supported both a 1-factor model and a 2-factor model comprising correlated Episodic Memory and Executive Function (EF) factors. Both models demonstrated strict invariance across TBI severity and OTC groups. Correlations between BTACT and criterion measures suggested that the BTACT memory indices predominantly reflect verbal episodic memory, whereas the BTACT EF factor correlated with a diverse range of cognitive tests. Although the EF factor and other BTACT indices showed significant relationships with TBI and TBI severity, some group effect sizes were larger for more comprehensive in-person cognitive tests than the BTACT. The BTACT is a promising, brief, phone-based cognitive screening tool for patients with TBI. Although the BTACT's memory items appear to index verbal Episodic Memory, items that purport to assess EFs may reflect a broader array of cognitive domains. The sensitivity of the BTACT to TBI severity is lower than domain-specific neuropsychological measures, suggesting it should not be used as a substitute for comprehensive, in-person cognitive testing at 6 months post-TBI.

BackgroundAlcohol, insulin resistance (IR), and hepatitis C (HCV) are all significant contributors to adverse outcomes of chronic liver disease. Latinos are disproportionately affected by these risk factors. We investigated the relationship between alcohol use and insulin action in a prospective cohort of Latino individuals with and without HCV.MethodsOne hundred fifty-three nondiabetic Latino individuals (60 HCV+, 93 HCV-) underwent clinical evaluation and metabolic testing; 56 had repeat testing over a median follow-up of 1.5 years. Peripheral IR and hepatic IR were measured via steady-state plasma glucose (SSPG) and endogenous glucose production during a two-step, 240-min insulin suppression test. Insulin secretion (IS) was measured using the graded glucose infusion test. Alcohol use was categorized as none, moderate (≤1 drink/day for women and ≤2 drinks/day for men), and heavy (>moderate). Multivariable models including HCV status assessed associations of alcohol use with baseline SSPG, hepatic IR and IS, and changes in these parameters over time.ResultsOverall, the median age was 44 years, 63.4% were male, 66.7% overweight/ obese, and 31.9% had heavy lifetime alcohol use while 60.4% had moderate lifetime alcohol use. SSPG and IS were similar by levels of alcohol use at baseline and alcohol use was not statistically significantly associated with change in these measures over time. However, lifetime daily heavy alcohol use (vs. not heavy, coef 2.4 μU-mg/kg-min-ml, p = 0.04) and HCV status (coef 4.4 μU-mg/kg-min-ml, p = 0.0003) were independently associated with higher baseline hepatic IR, and current heavy alcohol use was associated with greater change in hepatic IR in follow-up (coef 5.8 μU-mg/kg-min-ml, p = 0.03).ConclusionsIn this cohort of Latino individuals, lifetime and current heavy alcohol use influenced hepatic IR and its change over time. Strategies to decrease rates of heavy alcohol use or increase abstinence along with lifestyle modification and anti-HCV therapy to reduce metabolic risk are critical to prevent adverse liver and metabolic outcomes in Latino individuals.

OBJECTIVES: The objective was to determine the feasibility and effectiveness of cardiac magnetic resonance (CMR) cine and strain imaging before and after cardiac resynchronization therapy (CRT) for assessment of response and the optimal resynchronization pacing strategy. BACKGROUND: CMR with cardiac implantable electronic devices can safely provide high-quality right ventricular/left ventricular (LV) ejection fraction (RVEF/LVEF) assessments and strain. METHODS: CMR with cine imaging, displacement encoding with stimulated echoes for the circumferential uniformity ratio estimate with singular value decomposition (CURE-SVD) dyssynchrony parameter, and scar assessment was performed before and after CRT. Whereas the pre-CRT scan constituted a single imaging set with complete volumetric, strain, and scar imaging, multiple imaging sets with complete strain and volumetric data were obtained during the post-CRT scan for biventricular pacing (BIVP), LV pacing (LVP), and asynchronous atrial pacing modes by reprogramming the device outside the scanner between imaging sets. RESULTS: 100 CMRs with a total of 162 imaging sets were performed in 50 patients (median age 70 years [IQR: 50-86 years]; 48% female). Reduction in LV end-diastolic volumes (P = 0.002) independent of CRT pacing were more prominent than corresponding reductions in right ventricular end-diastolic volumes (P = 0.16). A clear dependence of the optimal CRT pacing mode (BIVP vs LVP) on the PR interval (P = 0.0006) was demonstrated. The LVEF and RVEF improved more with BIVP than LVP with PR intervals ≥240 milliseconds (P = 0.025 and P = 0.002, respectively); the optimal mode (BIVP vs LVP) was variable with PR intervals

It is important to measure quality of life (QoL) after traumatic brain injury (TBI), yet limited studies have compared QoL inventories. In 2579 TBI patients, orthopedic trauma controls, and healthy friend control participants, we compared the Quality of Life After Brain Injury-Overall Scale (QOLIBRI-OS), developed for TBI patients, to the Satisfaction with Life Scale (SWLS), an index of generic life satisfaction. We tested the hypothesis that group differences (TBI and orthopedic trauma vs. healthy friend controls) would be larger for the QOLIBRI-OS than the SWLS and that the QOLIBRI-OS would manifest more substantial changes over time in the injured groups, demonstrating more relevance of the QOLIBRI-OS to traumatic injury recovery. (1) We compared the group differences (TBI vs. orthopedic trauma control vs. friend control) in QoL as indexed by the SWLS versus the QOLIBRI-OS and (2) characterized changes across time in these two inventories across 1 year in these three groups. Our secondary objective was to characterize the relationship between TBI severity and QoL. As compared with healthy friend controls, the QOLIBRI reflected greater reductions in QoL than the SWLS for both the TBI group (all time points) and the orthopedic trauma control group (2 weeks and 3 months). The QOLIBRI-OS better captured expected improvements in QoL during the injury recovery course in injured groups than the SWLS, which demonstrated smaller changes over time. TBI severity was not consistently or robustly associated with self-reported QoL. The findings imply that, as compared with the SWLS, the QOLIBRI-OS appears to identify QoL issues more specifically relevant to traumatically injured patients and may be a more appropriate primary QoL outcome measure for research focused on the sequelae of traumatic injuries.

Patients with early-onset Alzheimer's disease (EOAD) are commonly excluded from large-scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial-ready network. LEADS will follow 400 amyloid beta (Aβ)-positive EOAD, 200 Aβ-negative EOnonAD that meet National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age-matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [18 F]Florbetaben and [18 F]Flortaucipir positron emission tomography (PET), lumbar puncture, and blood draw for DNA, RNA, plasma, serum and peripheral blood mononuclear cells, and post-mortem assessment. To develop more effective AD treatments, scientists need to understand the genetic, biological, and clinical processes involved in EOAD. LEADS will develop a public resource that will enable future planning and implementation of EOAD clinical trials.

We investigated whether clinically normal older adults with remote, mild traumatic brain injury (mTBI) show evidence of higher cortical Aβ burden. Our study included 134 clinically normal older adults (age 74.1 ± 6.8 years, 59.7% female, 85.8% white) who underwent Aβ positron emission tomography (Aβ-PET) and who completed the Ohio State University Traumatic Brain Injury Identification questionnaire. We limited participants to those reporting injuries classified as mTBI. A subset (N = 30) underwent a second Aβ-PET scan (mean 2.7 years later). We examined the effect of remote mTBI on Aβ-PET burden, interactions between remote mTBI and age, sex, and APOE status, longitudinal Aβ accumulation, and the interaction between remote mTBI and Aβ burden on memory and executive functioning. Of 134 participants, 48 (36%) reported remote mTBI (0, N = 86; 1, N = 31, 2+, N = 17; mean 37 ± 23 years since last mTBI). Effect size estimates were small to negligible for the association of remote mTBI with Aβ burden (p = .94, η2

BackgroundThe status of the systemic right ventricular coronary microcirculation in hypoplastic left heart syndrome (HLHS) is largely unknown. It is presumed that the systemic right ventricle's coronary microcirculation exhibits unique pathophysiological characteristics of HLHS in Fontan circulation. The present study sought to quantify myocardial blood flow by cardiac magnetic resonance imaging and evaluate the determinants of microvascular coronary dysfunction and myocardial ischemia in HLHS.MethodsOne hundred nineteen HLHS patients (median age, 4.80 years) and 34 healthy volunteers (median age, 5.50 years) underwent follow-up cardiac magnetic resonance imaging ≈1.8 years after total cavopulmonary connection. Right ventricle volumes and function, myocardial perfusion, diffuse fibrosis, and late gadolinium enhancement were assessed in 4 anatomic HLHS subtypes. Myocardial blood flow (MBF) was quantified at rest and during adenosine-induced hyperemia. Coronary conductance was estimated from MBF at rest and catheter-based measurements of mean aortic pressure (n=99).ResultsHyperemic MBF in the systemic ventricle was lower in HLHS compared with controls (1.89±0.57 versus 2.70±0.84 mL/g per min; P

The Glasgow Outcome Scale (GOS) in its original or extended (GOSE) form is the most widely used assessment of global disability in traumatic brain injury (TBI) research. Several publications have reported concerns about assessor scoring inconsistencies, but without documentation of contributing factors. We reviewed 6801 GOSE assessments collected longitudinally, across 18 sites in the 5-year, observational Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. We recorded error rates (i.e., corrections to a section or an overall rating) based on site assessor documentation and categorized scoring issues, which then informed further training. In cohort 1 (n = 1261; February 2014 to May 2016), 24% of GOSEs had errors identified by central review. In cohort 2 (n = 1130; June 2016 to July 2018), acquired after curation of cohort 1 data, feedback, and further training of site assessors, the error rate was reduced to 10%. GOSE sections associated with the most frequent interpretation and scoring difficulties included whether current functioning represented a change from pre-injury (466 corrected ratings in cohort 1; 62 in cohort 2), defining dependency in the home and community (163 corrections in cohort 1; three in cohort 2) and return to work/school (72 corrections in cohort 1; 35 in cohort 2). These results highlight the importance of central review in improving consistency across sites and over time. Establishing clear scoring criteria, coupled with ongoing guidance and feedback to data collectors, is essential to avoid scoring errors and resultant misclassification, which carry potential to result in "failure" of clinical trials that rely on the GOSE as their primary outcome measure.

BackgroundPlasma tau phosphorylated at threonine 217 (p-tau217) and plasma tau phosphorylated at threonine 181 (p-tau181) are associated with Alzheimer's disease tau pathology. We compared the diagnostic value of both biomarkers in cognitively unimpaired participants and patients with a clinical diagnosis of mild cognitive impairment, Alzheimer's disease syndromes, or frontotemporal lobar degeneration (FTLD) syndromes.MethodsIn this retrospective multicohort diagnostic performance study, we analysed plasma samples, obtained from patients aged 18-99 years old who had been diagnosed with Alzheimer's disease syndromes (Alzheimer's disease dementia, logopenic variant primary progressive aphasia, or posterior cortical atrophy), FTLD syndromes (corticobasal syndrome, progressive supranuclear palsy, behavioural variant frontotemporal dementia, non-fluent variant primary progressive aphasia, or semantic variant primary progressive aphasia), or mild cognitive impairment; the participants were from the University of California San Francisco (UCSF) Memory and Aging Center, San Francisco, CA, USA, and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL; 17 sites in the USA and two in Canada). Participants from both cohorts were carefully characterised, including assessments of CSF p-tau181, amyloid-PET or tau-PET (or both), and clinical and cognitive evaluations. Plasma p-tau181 and p-tau217 were measured using electrochemiluminescence-based assays, which differed only in the biotinylated antibody epitope specificity. Receiver operating characteristic analyses were used to determine diagnostic accuracy of both plasma markers using clinical diagnosis, neuropathological findings, and amyloid-PET and tau-PET measures as gold standards. Difference between two area under the curve (AUC) analyses were tested with the Delong test.FindingsData were collected from 593 participants (443 from UCSF and 150 from ARTFL, mean age 64 years [SD 13], 294 [50%] women) between July 1 and Nov 30, 2020. Plasma p-tau217 and p-tau181 were correlated (r=0·90, p

We assessed sex differences in amyloid- and tau-PET retention in 119 amyloid positive patients with mild cognitive impairment or Alzheimer's disease (AD) dementia. Patients underwent 3T-MRI, 11C-PIB amyloid-PET and 18F-Flortaucipir tau-PET. Linear ordinary least squares regression models tested sex differences in Flortaucipir-PET SUVR in a summary temporal region of interest as well as global PIB-PET. No sex differences were observed in demographics, Clinical Dementia Rating Sum of Boxes (CDR-SoB), Mini-Mental State Exam (MMSE), raw episodic memory scores, or cortical thickness. Females had higher global PIB SUVR (ηp²=.043, p=.025) and temporal Flortaucipir SUVR (ηp²=.070, p=.004), adjusting for age and CDR-SoB. Sex differences in temporal Flortaucipir-PET remained significant when controlling additionally for PIB SUVR and APOE4 status (ηp²=.055, p=.013), or when using partial volume-corrected data. No sex differences were present in areas of known Flortaucipir off-target binding. Overall, females demonstrated greater AD regional tau-PET burden than males despite clinical comparability. Further characterization of sex differences will provide insight into AD pathogenesis and support development of personalized therapeutic strategies.

Co-pathologies play an important role in the expression of the Alzheimer's disease clinical phenotype and may influence treatment efficacy. Early-onset Alzheimer's disease, defined as manifesting before age 65, is viewed as a relatively pure form of Alzheimer's disease with a more homogeneous neuropathological substrate. We sought to compare the frequency of common neuropathological diagnoses in a consecutive autopsy series of 96 patients with early-onset Alzheimer's disease (median age of onset = 55 years, 44 females) and 48 with late-onset Alzheimer's disease (median age of onset = 73 years, 14 females). The UCSF Neurodegenerative Disease Brain Bank database was reviewed to identify patients with a primary pathological diagnosis of Alzheimer's disease. Prevalence and stage of Lewy body disease, limbic age-related TDP-43 encephalopathy (LATE), argyrophilic grain disease, hippocampal sclerosis, cerebral amyloid angiopathy, and vascular brain injury were compared between the two cohorts. We found at least one non-Alzheimer's disease pathological diagnosis in 98% of patients with early-onset Alzheimer's disease (versus 100% of late onset), and the number of comorbid diagnoses per patient was lower in early-onset than in late-onset Alzheimer's disease (median = 2 versus 3, Mann-Whitney Z = 3.00, P = 0.002). Lewy body disease and cerebral amyloid angiopathy were common in both early and late onset Alzheimer's disease (cerebral amyloid angiopathy: 86% versus 79%, Fisher exact P = 0.33; Lewy body disease: 49% versus 42%, P = 0.48, respectively), although amygdala-predominant Lewy body disease was more common in early than late onset Alzheimer's disease (22% versus 6%, P = 0.02). In contrast, LATE (35% versus 8%, P