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Older adults walk with less push-off power than younger adults. Principally attributed to plantar flexor dysfunction, growing evidence implicates interactions between the foot and ankle as critical for generating effective push-off. Our purposes were to measure age effects on foot–ankle mechanical transmission (FAMT, ie, the ratio between metatarsal phalangeal extension and medial gastrocnemius fascicle length change), and its association with ankle push-off during walking. We hypothesized that (1) FAMT would be lesser in older adults and (2) lesser FAMT would positively correlate with slower preferred speeds and reduced ankle push-off intensity. Fourteen younger adults (25 [6] y) and 15 older adults (71 [5] y) participated. Older adults had 45% to 48% lesser FAMT than younger adults from 0° to 30° metatarsal phalangeal extension—an age-related difference that was not evident from 30° to 60° metatarsal phalangeal extension. However, we did not find any significant correlations with walking outcomes. Assuming our findings can be replicated in future studies and represent a genuine phenomenon of relevance to the biomechanics of aging gait, we suspect that compensations may be discovered in older adults to explain this lack of significance. Future work should include measures of muscle activities and foot mechanics during walking and/or perform more controlled comparisons at fixed speeds. [ABSTRACT FROM AUTHOR]

The Performance Index (P-Index) is a measure for evaluating mobility-related dual-task performance in older adults. The identification of specific clinicodemographic factors predictive of P-Index scores, however, remains unclear. This cross-sectional study analyzed data from 120 community-dwelling older adults (average age 71.3 ± 11.23 years) to explore clinicodemographic variables that influence P-Index scores during the instrumented timed up and go test. Unadjusted analyses suggested several factors, including age, gender, body mass index, Mini-Mental Status Examination scores, functional reach test performance, history of falls, ethnicity, Geriatric Depression Scale scores, alcohol consumption, and educational levels, as potential predictors of P-Index. However, adjusted multinomial multiple regression analysis revealed Geriatric Depression Scale and Mini-Mental Status Examination scores as the exclusive independent predictors of P-Index classifications, segmented into high, intermediate, or low (percentiles ≤ 25, 26–74, or ≥ 75, respectively). A significant association was observed between the manifestation of depressive symptoms, lower Mini-Mental Status Examination scores, and reduced cognitive–motor performance. The findings implicate depressive symptoms and low cognitive performance as substantial impediments to optimal dual-task mobility within this cohort. Further studies are warranted to examine the efficacy of cognitive stimulation and antidepressant therapy, in augmenting mobility-related dual-task performance among older adults. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the effects of multicomponent training on adropin, endothelial function, insulin resistance, and sleep quality in overweight older adults. In this randomized controlled study, 40 overweight older adults were randomly divided into training and control groups. The multicomponent training program including aerobic, resistance, and balance exercise was followed for 8 weeks, 3 days a week. Study variables were measured 48 hr before and after the intervention. After 8 weeks of multicomponent training, adropin (p =.01), nitric oxide (p =.01), and maximal oxygen uptake (VO2max; p =.002) increased, and glucose (p =.001), insulin (p =.001), insulin resistance (p =.01), systolic blood pressure (p =.01), and sleep disorders (p =.01) decreased significantly. Also, Pearson's test results showed a significant inverse relationship between adropin level (p =.01 and r = −.55) and glucose (p =.01 and r = −.51) with sleep disorders. It seems that multicomponent training increases adropin and improves insulin resistance, endothelial function, and sleep quality in older adults. [ABSTRACT FROM AUTHOR]

Background: Pickleball has grown tremendously in recent years, yet little evidence exists regarding pickleball-related injuries. This scoping review extends current work on pickleball participation by identifying positive and negative health effects associated with the sport. We summarize how pickleball impacts the health and well-being of adult participants. Methods: Searches were conducted on MEDLINE, CINAHL, ProQuest Nursing, ERIC, SPORTDiscus, PsycINFO, Scopus, CBCA Complete, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and ProQuest Dissertations and Theses. Selected studies considered aspects of health and/or well-being of adult pickleball participants. Using the population/concept/context framework, participants were healthy, able-bodied adults 18 years of age or over, who had played pickleball at least once. The positive and negative outcomes of pickleball on participants' health and well-being (concept) within the context of pickleball participation were examined. Full-text articles written in English since 2013 were included. Extracted data were tabulated, and a descriptive summary with thematic analysis was completed. Results: This scoping review comprised 27 articles that met the inclusion criteria. Pickleball is promising as an exercise intervention for all adults, and there is evidence of positive social and psychological effects, and health and fitness benefits to participating in pickleball by older adults. Conclusions: Although we are still in the early stages of studying pickleball, there have been some documented health benefits of using the sport as a physical exercise intervention for adults. More research is needed on the types, prevalence, and severity of pickleball injuries and the sport's impact on younger players. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the behavior of hybrid abutment crowns fabricated from monolithic lithium disilicate ceramic (LDC) and to compare the influence of different in vitro ar>ficial aging protocols. Materials and Methods: A total of 32 monolithic hybrid abutment crowns of monolithic LDC were fabricated. Of these, 24 were ar>ficially aged using three different protocols up to a 20 year simula>on (1.2 × 106, 2.4 × 106, 4.8 × 106 chewing cycles, thermocycling), a control group underwent no ar>ficial aging (n = 8, N = 32). Load-to-failure tests were conducted for all specimens, and failure values were compared (P < .05). Results: All specimens passed in vitro aging. Mean failure load values between 532.6 and 562.8 N were found but did neither differ significantly among the test groups nor from the control group. Conclusions: Within the limita>ons of this in vitro pilot study, hybrid abutment crowns manufactured from monolithic LDC seem to offer appropriate long-las>ng mechanical stability over a simula>on period up to 20 years. The failure values and complica>on paTern seem to b e independent of several aging protocols in this test set-up. [ABSTRACT FROM AUTHOR]

Purpose: Loss of muscle power has a significant impact on mobility in geriatric populations, so this study sought to determine the extent and time course of performance decline in power-centric events throughout the life span via retrospective analyses of masters and elite track-and-field data. Methods: Four track-and-field events were selected based on maximal power output: the 100-m dash, long jump, high jump, and triple jump. Elite and masters athlete data were gathered from the World Masters Outdoor Championships and the International Amateur Athletic Federation World Athletics Championships (17,945 individual results). Data were analyzed by fitting individual and group results to quadratic and linear models. Results: Average age of peak performance in all events was 27.8 (0.8) years for men and 28.3 (0.8) years for women. Athlete performance decline best matched a linear model for the 5 years following peak performance (mean R2 =.68 [.20]) and for ages 35–60, but best matched a quadratic model for ages 60–90 and 35–90 (mean R2 =.75 [.12]). The average rate of decline for the masters data ages 35–60 ranged from 0.55% per year for men's 100-m dash to 1.04% per year for women's long jump. A significant age × sex interaction existed between men and women, with men declining faster throughout life in all events except the 100-m dash. Conclusions: Performance decline begins in the early 30s and is linear through middle age. This pattern of decline provides a basis for further research on power-decline pathophysiology and preventive measures starting in the 30s. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the influence of knee joint range of motion (RoM) on the torque–velocity relationship and fatigue in the knee extensor muscles of 7 young (median = 26 y) and 7 older (68 y) adults. Each leg was assigned a RoM (35° or 75°) over which to perform a torque–velocity protocol (maximal isokinetic contractions, 60–300°·s−1) and a fatigue protocol (120 maximal contractions at 120°·s−1, 0.5 Hz). Six older participants were unable to reach 300°·s−1 over 35°. Therefore, the velocity eliciting 75% of peak torque at 60°·s−1 (V75, °·s−1) was calculated for each RoM from a fit of individual torque–velocity curves (60–240°·s−1), and ΔV75 (35°–75°) was determined. Fatigue (final torque/initial torque) was used to calculate Δfatigue (35°–75°). ΔV75 was not different from 0 in young (−28.3°·s−1 [−158.6 to 55.7], median [range], P =.091) or older (−18.5°·s−1 [−95.0 to 23.9], P =.128), with no difference by age (P =.710). In contrast, fatigue was greater for 75° in young (Δfatigue = 25.9% [17.5–30.3], P =.018) and older (17.2% [11.9–52.9], P =.018), with no effect of age (P =.710). These data indicate that, regardless of age, RoM did not alter the torque–velocity relationship between 60 and 240°·s−1, and fatigue was greater with a larger RoM. [ABSTRACT FROM AUTHOR]

Resistance training is used to combat skeletal muscle function decline in older adults. Few studies have been designed specific for females, resulting in very limited treatment options for skeletal muscle atrophy in aging women. Here, we analyzed the gene expression profiles of skeletal muscle samples from sedentary young women, sedentary older women, and resistance-trained older women, using microarray data from public database. A total of 45 genes that were differentially expressed during female muscle aging and reversed by resistance training were identified. Functional and pathway enrichment analysis, protein–protein interaction network analysis, and receiver operating characteristic analysis were performed to reveal the key genes and pathways involved in the effects of resistance training on female muscle aging. The collagen genes COL1A1, COL3A1, and COL4A1 were identified important regulators of female muscle aging and resistance training, by modulating multiple signaling pathways, such as PI3 kinase-Akt signaling, focal adhesions, extracellular matrix-receptor interactions, and relaxin signaling. Interestingly, the expression of CDKN1A and TP63 were increased during aging, and further upregulated by resistance training in older women, suggesting they may negatively affect resistance training outcomes. Our findings provide novel insights into the molecular mechanisms of resistance training on female muscle aging and identify potential biomarkers and targets for clinical intervention. [ABSTRACT FROM AUTHOR]

Background: Retirement transition has been shown to associate with changes in physical activity (PA) and self-rated health (SRH), but their interrelationship is less studied. The aim was to investigate changes in accelerometer-measured total PA, moderate to vigorous PA (MVPA), and sedentary time across retirement transition as a predictor of SRH. Methods: Data from the Swedish Retirement Study and the Finnish Retirement and Aging study were harmonized and pooled. Data from 3 waves (about 12 mo apart) were included: 1 preretirement (wave 1) and 2 postretirement follow-ups (wave 2–3). A totally of 245 participants (27% men) were included. Thigh-worn accelerometers were used to collect data for PA variables (wave 1–2), and SRH was obtained from the questionnaire (wave 1–3). Results: Between wave 1 and 2, total PA decreased with 11 (CI, −22 to −1) minutes per day, MVPA was stable (0 [CI, −3 to 3] min), and sedentary time decreased nonsignificantly with 9 (CI, −20 to 1) minutes. SRH changed between all 3 waves (all P <.001). At preretirement, 10 more minutes of MVPA was associated with greater odds of better SRH when adjusting for accelerometer wear-time, cohort, sex, age, and occupational status (odds ratio: 1.11 [95% CI, 1.02–1.22]). This association was no longer statistically significant when additionally adjusting for marital status, body mass index, and smoking. No significant associations were observed between changes in the PA variables during retirement transition and SRH at postretirement follow-ups. Conclusions: This study showed a cross-sectional association between MVPA and greater odds of reporting better SRH before retirement. No longitudinal associations were observed between changes in the PA variables from before to after retirement and later changes in SRH. [ABSTRACT FROM AUTHOR]

Large-amplitude thermal excursions imposed on deeply supercooled liquids modulate the nonlinear time evolution of their structural rearrangements. The consequent aftereffects are treated within a Wiener–Volterra expansion in laboratory time that allows one to calculate the associated physical-aging and thermal response functions. These responses and the corresponding higher-harmonic susceptibilities are illustrated using calculations based on the Tool–Narayanaswamy–Moynihan (TNM) model. The conversion from laboratory to material time is thoroughly discussed. Similarities and differences to field-induced higher-harmonic susceptibilities are illustrated using Lissajous and Cole–Cole plots and discussed in terms of aging nonlinearity parameters. For the Lissajous plots, banana-type shapes emerge, while the Cole–Cole plots display cardioidic and other visually appealing patterns. For application beyond the regime in which conventional single-parameter aging concepts work, the Wiener–Volterra material-time-series is introduced as the central tool. Calculations and analyses within this general framework in conjunction with suitable choices of higher-order memory kernels and employing correspondingly extended TNM models yield at least qualitative agreement with recent large-perturbation physical aging experiments. Implications for differential scanning calorimetry and related methods are discussed. The introduced concepts and analyses provide a solid foundation for a generalized description of nonlinear thermal out-of-equilibrium dynamics of glass forming materials, differing from the nonlinear responses known from rheology and dielectric spectroscopy. [ABSTRACT FROM AUTHOR]

This study evaluated physical activity interventions designed for individuals with visual impairments and sought to guide health intervention scientists aiming to promote physical activity in this demographic. We delved into the specifics of participants' visual impairments, intervention features, accommodation approaches, and replicability prospects. The search spanned four databases, namely PubMed, CINAHL, SportDiscus, and Scopus, providing a wide scope and diversity of potential studies. There were no restrictions on publication years. We reviewed 13 studies, totaling 15 interventions. A consensus on visual-impairment definitions remains elusive, and the intervention dosages displayed variability. Notably, 66.7% (n = 7) integrated behavior-change techniques to amplify physical activity levels. Multiple studies employed audio descriptions as an accommodation method. While most studies provided adequate information for potential replication, detailed study protocols were frequently absent. It is essential for developed interventions to be persistently evaluated and fine-tuned to optimize results. [ABSTRACT FROM AUTHOR]

This case study assessed body composition, muscle strength, cardiorespiratory fitness, and metabolic health of the present female world champion powerlifter in the 70+ age category who started resistance exercise training at 63 years of age with no prior experience with structured exercise training. Measures of body composition (magnetic resonance imaging, computed tomography, and dual-energy X-ray absorptiometry scanning, leg volume); strength (one-repetition maximum leg press and extension, maximum voluntary contraction, and handgrip strength); physical function (short physical performance battery); cardiorespiratory fitness (peak oxygen consumption); and metabolic health (oral glucose tolerance test) were assessed. In addition, a muscle biopsy was collected to assess muscle fiber type distribution and cross-sectional area (CSA). Where possible, data were compared with previously (un)published sex- and age-matched data using z scores. Skeletal muscle mass index was calculated by dividing limb muscle mass by height squared. Data from the control groups are expressed as mean ± 95% confidence interval. Our participant (age: 71 years; body mass: 64.5 kg; body mass index: 27.6 kg/m2) reported a good bone mineral density of 1.09 g/cm2 (T score between −1 and +1) and very low values of abdominal and organ body fat (i.e., between 20% and 70% lower compared with a reference group of postmenopausal women). In addition, she showed a 33% greater skeletal muscle mass index when compared with healthy, older female control subjects (7.9 vs. 5.9 [5.7–6.2] kg/m2; n = 61) as well as 37% greater muscle quadriceps CSA (63.8 vs. 46.6 [44.5–48.7] cm2; n = 48) and 46% greater Type II muscle fiber CSA (4,536 vs. 3,097 [2,707–3,488] μm2; n = 19). Absolute leg press muscle strength was 36% greater (190 vs. 140 [132–147] kg; n = 30) and handgrip strength was 33% greater (33 vs. 25 [23–26] kg; n = 48) when compared with healthy, age-matched controls. In conclusion, even for resistance exercise naïve individuals, starting exercise at an advanced age can lead to improvements in body composition and muscle strength allowing older adults to reduce the risk for developing metabolic syndrome, live independently, and even compete at a world class level. [ABSTRACT FROM AUTHOR]

Background: Walking activity has been associated with reduction in the development of chronic disease, cognitive and physical function impairment, disability, and mortality. The objective of this study was to examine the relationship between walking activity and physical function over 9 years of follow-up among Mexican Americans aged 78 years and older. Methods: Participants (N = 998) were from the Hispanic Established Population for the Epidemiologic Study of the Elderly (2007–2016). Measures included walking activity duration and frequency, socio-demographics, body mass index, medical conditions, pain, depressive symptoms, limitation in activities of daily living, and the Mini-Mental State Examination. Low physical function was defined as scoring <7 on the Short Physical Performance Battery. At baseline, participants were grouped into nonwalkers (n = 653), walked <150 minutes/week (n = 144), and walked 150 minutes/week or more (n = 201). A Generalized Estimating Equation model was used to estimate the odds ratio and 95% CI of low physical performance as a function of walking activity status. Results: Compared with nonwalkers, participants walking < 150 minutes/week had lower odds (odds ratio = 0.66, 95% CI, 0.51–0.86) of low physical function over time, after controlling for all covariates, as did those walking ≥ 150 minutes/week (odds ratio = 0.54, 95% CI, 0.41–0.71). Conclusions: Mexican American older adults who engage in any walking activity are at reduced risk of low physical function, even those with disability. Interventions at the individual and community level are recommended to reduce physical function impairment, even in those with preexisting medical conditions or disability. [ABSTRACT FROM AUTHOR]

Falls are very serious health concerns among older adults. Providing additional cutaneous and proprioceptive feedback to older adults may enhance their balance control and therefore reduce the incidents of falls. This study aimed to investigate the acute and acclimated effect of wearing waist-to-above-ankle compression garments (CGs) on balance control in community-dwelling older adults. Thirty-one older adults participated in the study. The Timed Up and Go, Berg Balance Scale, and the Fall Risk Test of the Biodex Balance System were used in a random order to examine balance control in three testing sessions 1 week apart. Results indicated wearing CGs had a significant impact on the Timed Up and Go test (p <.001), Berg Balance Scale (p =.001), and the Fall Risk Test (p =.001). For the Timed Up and Go test, participants exhibited significant improvement in both the acute (8.68 vs. 7.91 s) and acclimated effect (7.91 vs. 7.41 s) of wearing CGs. For the Berg Balance Scale, participants showed significant improvement after wearing CGs for 1 week in comparison to the no CGs condition (55.77 vs. 55.39 points). For the Fall Risk Test, participants showed a significant improvement in the acute effect of wearing CGs in comparison to the no CGs condition (1.55° vs. 1.31°). This exploratory study showed that wearing waist-to-above-ankle CGs provided a positive impact on balance control in healthy community-dwelling older adults. It lays the foundation for future studies with a larger sample size to investigate the potential benefits of wearing CGs in individuals with balance control deficits and/or other comorbidities. [ABSTRACT FROM AUTHOR]

Changes in neuronal inhibition have been implicated in age-related declines in sensorimotor performance. While indirect evidence suggests that inhibitory mechanisms are also involved in rhythm entrainment, this association has not been tested. Using magnetic resonance spectroscopy, we tested the association between dorsomedial frontal GABA+/H2O concentrations and musical rhythm production in healthy younger (n = 14; 18-35) and older (n = 12; 55-79) adults, hypothesizing that lower GABA+/H2O concentrations would be associated with increased timing error, particularly on more difficult exercises, and intra-individual variability (quantified via mean successive squared difference (MSSD)). Rhythm learning exercises were presented in order of complexity. Linear mixed effects modeling revealed GABA+/H2O-by-exercise number interaction (β = -0.59, p = 0.006) such that participants with lower GABA+/H2O showed greater performance decrement with increasing exercise difficulty. GABA+/H2O trended toward an inverse association with MSSD (β = -0.25, p = 0.089), such that higher GABA+/H2O was associated with lower variability in performance. Older age was associated with increased absolute timing error (β = 0.66, p

As of 2023, it is estimated that 6.7 million individuals in the United States live with Alzheimer's disease (AD). Prior research indicates that AD disproportionality affects females; females have a greater incidence rate, perform worse on a variety of neuropsychological tasks, and have greater total brain atrophy. Recent research shows that hippocampal functional connectivity differs by sex and may be related to the observed sex differences in AD, and apolipoprotein E (ApoE) ε4 carriers have reduced hippocampal functional connectivity. The purpose of this study was to determine if the ApoE genotype plays a role in the observed sex differences in hippocampal functional connectivity in Alzheimer's disease. The resting state fMRI and T2 MRI of individuals with AD (n = 30, female = 15) and cognitively normal individuals (n = 30, female = 15) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed using the functional connectivity toolbox (CONN). Our results demonstrated intrahippocampal functional connectivity differed between those without an ε4 allele and those with at least one ε4 allele in each group. Additionally, intrahippocampal functional connectivity differed only by sex when Alzheimer's participants had at least one ε4 allele. These results improve our current understanding of the role of the interacting relationship between sex, ApoE genotype, and hippocampal function in AD. Understanding these biomarkers may aid in the development of sex-specific interventions for improved AD treatment.

BackgroundIndividuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21.MethodsWe examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data.FindingsFor both cohorts, the prevalence of mosaicism was

We examined the relationship between subjective and objective sleep outcomes and loneliness in older women at risk for Alzheimer's disease (AD). Our sample consisted of 39 participants (aged 65+) with mild cognitive deficits who completed the UCLA Loneliness Scale, the Pittsburgh Sleep Quality Index (PSQI), and an at home sleep test, to determine presence of obstructive sleep apnea. Based on sleep quality scores, individuals categorized as "poor sleepers" had significantly higher loneliness scores than "good sleepers." However, total loneliness scores did not significantly differ between groups with or without sleep apnea. We found that higher loneliness was significantly associated to lower habitual sleep efficiency and sleep duration and was also influenced by use of sleep medication. Our findings suggest that increased loneliness relates to worse subjective sleep quality, but not to sleep apnea. These findings suggest that combined interventions targeting loneliness and sleep quality may be important for older women.

Measures of life outlook in older adults have been investigated in connection to pain, as both pain management and outlook are important factors of successful aging. We hypothesized that higher pain is associated with lower optimism among community-dwelling older adults. We utilized data from the UC San Diego Successful Aging Evaluation (SAGE), a prospective longitudinal cohort study initiated in 2010, to evaluate the relationship between pain and optimism in 378 community-dwelling adults aged ≥50 years. We used the revised Life Orientation Test (LOT-R) to measure optimism and three pain subscales-PROMIS Pain Interference, PROMIS Pain Intensity, and MOS 36-Item Short-Form Health Survey (SF-36)-as pain measures. Regression analyses reveal negative relationships between pain and optimism for all three pain scales, with regression coefficients of -0.277 (p

Background: Surveys of internet panels such as Amazon’s Mechanical Turk (MTurk) are common in health research. Nonresponse in longitudinal studies can limit inferences about change over time. Objective: This study aimed to (1) describe the patterns of survey responses and nonresponse among MTurk members with back pain, (2) identify factors associated with survey response over time, (3) assess the impact of nonresponse on sample characteristics, and (4) assess how well inverse probability weighting can account for differences in sample composition. Methods: We surveyed adult MTurk workers who identified as having back pain. We report participation trends over 3 survey waves and use stepwise logistic regression to identify factors related to survey participation in successive waves. Results: A total of 1678 adults participated in wave 1. Of those, 983 (59%) participated in wave 2 and 703 (42%) in wave 3. Participants who did not drop out took less time to complete previous surveys (30 min vs 35 min in wave 1, P

Music-evoked autobiographical memories (MEAMs) are typically elicited by music that listeners have heard before. While studies that have directly manipulated music familiarity show that familiar music evokes more MEAMs than music listeners have not heard before, music that is unfamiliar to the listener can also sporadically cue autobiographical memory. Here we examined whether music that sounds familiar even without previous exposure can produce spontaneous MEAMs. Cognitively healthy older adults (N = 75, ages 65-80 years) listened to music clips that were chosen by researchers to be either familiar or unfamiliar (i.e., varying by prior exposure). Participants then disclosed whether the clip elicited a MEAM and later provided self-reported familiarity ratings for each. Self-reported familiarity was positively associated with the occurrence of MEAMs in response to familiar, but not the unfamiliar, music. The likelihood of reporting MEAMs for music released during youth (i.e., the "reminiscence bump") relative to young adulthood (20-25 years) included both music released during participants' adolescence (14-18 years) and middle childhood (5-9 years) once self-reported familiarity was accounted for. These developmental effects could not be accounted for by music-evoked affect. Overall, our results suggest that the phenomenon of MEAMs hinges upon both perceptions of familiarity and prior exposure.

IntroductionThe potential utility of subjective cognitive decline (SCD) as an early risk marker of Alzheimer's disease and related dementias is under consideration. We examined associations between SCD and cognitive change among middle-aged and older Hispanic/Latino adults living in the United States.MethodsThe short-form Everyday Cognition Scale (ECog-12) was assessed to generate global, executive function, and memory-related SCD scores. We used survey generalized regressions to model the change in learning, memory, verbal fluency, executive function, and global cognitive performance over 7 years as a function of SCD (at Visit 2).ResultsThe mean age was 56.37 ± 8.10 years at Visit 1 (n = 6225). Higher ECog-12 was associated with greater decline in global cognitive performance (ECog-12 global: B = -0.17, standard error [SE] = 0.02; ECog-12 executive: B = -0.15, SE = 0.02; ECog-12 memory: B = -0.14, SE = 0.02, p's

This study investigates the efficacy of predicting age-related macular degeneration (AMD) activity through deep neural networks (DNN) using a cross-instrument training dataset composed of Optical coherence tomography-angiography (OCTA) images from two different manufacturers. A retrospective cross-sectional study analyzed 2D vascular en-face OCTA images from Heidelberg Spectralis (1478 samples: 1102 training, 276 validation, 100 testing) and Optovue Solix (1003 samples: 754 training, 189 validation, 60 testing). OCTA scans were labeled based on clinical diagnoses and adjacent B-scan OCT fluid information, categorizing activity into normal, dry AMD, active wet AMD, and wet AMD in remission. Experiments explored cross-instrument disease classification using separate and combined datasets for training the DNN. Testing involved 100 Heidelberg and 60 Optovue samples. Training on Heidelberg data alone yielded 73% accuracy on Heidelberg images and 60% on Optovue images. Training on Optovue data alone resulted in 34% accuracy on Heidelberg and 85% on Optovue images. Combined training data from both instruments achieved 78% accuracy on Heidelberg and 76% on Optovue test sets. Results indicate that cross-instrument classifier training demonstrates high classification prediction accuracy, making cross-instrument training viable for future clinical applications. This implies that vascular morphology in OCTA can predict disease progression.

The tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. The primary tauopathies meet the definition of rare diseases in the United States. There is no approved treatment for primary tauopathies. In this context, designing the most efficient development programs to translate promising targets and treatments from preclinical studies to early-phase clinical trials is vital. In September 2022, the Rainwater Charitable Foundation convened an international expert workshop focused on the translation of tauopathy therapeutics through early-phase trials. Our report on the workshop recommends a framework for principled drug development and a companion lexicon to facilitate communication focusing on reproducibility and achieving common elements. Topics include the selection of targets, drugs, biomarkers, participants, and study designs. The maturation of pharmacodynamic biomarkers to demonstrate target engagement and surrogate disease biomarkers is a crucial unmet need. HIGHLIGHTS: Experts provided a framework to translate therapeutics (discovery to clinical trials). Experts focused on the "5 Rights" (target, drug, biomarker, participants, trial). Current research on frontotemporal degeneration, progressive supranuclear palsy, and corticobasal syndrome therapeutics includes 32 trials (37% on biologics) Tau therapeutics are being tested in Alzheimer's disease; primary tauopathies have a large unmet need.

PurposeTo investigate sex-based differences in inflammation-related biomarkers on spectral-domain OCT.DesignCross-sectional study.ParticipantsPatients with diabetic macular edema (DME) between February 1, 2019, and March 31, 2023, without intravitreal anti-VEGF injection within the previous 6 months.MethodsWe reviewed each patient's medical record for age, biological sex, race and ethnicity, most recent glycated hemoglobin A1c (HbA1c) level, visual acuity (VA), and central macular thickness (CMT). OCT biomarkers that have been found in literature to be associated with inflammation, including disorganization of retinal inner layers (DRIL), retinal hyperreflective retinal foci (HRFs), hyperreflective choroidal foci (HCFs), subfoveal neuroretinal detachment (SND), and perturbation in retinal nerve fiber layer thickness, ganglion cell layer thickness, and inner nuclear layer (INL) thickness were evaluated by graders masked to the clinical characteristics of the patients. We performed multivariable regression analyses with the OCT biomarkers as the outcome variables and sex, age, HbA1c, and CMT as independent variables.Main outcome measuresOCT inflammation-related biomarkers, as listed above.ResultsFemale patients were, on average, 2 years older than male patients (P = 0.041). There were no significant differences in race and ethnicity, HbA1c, VA, or CMT between male and female patients. After controlling for age, HbA1c, and CMT, we found male sex to be associated with more HRF (incidence rate ratio [IRR] = 1.19; 95% confidence interval [CI] = 1.10-1.29), more HCF (odds ratio = 2.01; 95% CI = 1.12-3.64), and thicker INL (7 μm thicker in males; 95% CI = 2-12). Sex was not a significant predictor for either DRIL or SND in the multivariable regression models. Patients with higher HbA1c were more likely to have more HRF (IRR = 1.02 per 1 point increase; 95% CI = 1.00-1.04) after controlling for other factors.ConclusionsMale sex was correlated with more inflammation-related biomarkers on OCT including more HRF, more HCF, and thicker INL, after accounting for age, glycemic control, and amount of DME. Further studies are needed to evaluate the potential implications of these sex-based differences for individualized treatment.Financial disclosuresProprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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.

BackgroundBreast arterial calcification (BAC) on mammograms has emerged as a biomarker of women's cardiovascular disease (CVD) risk, but there is a lack of quantification tools and clinical outcomes studies.ObjectivesThis study assessed the association of BAC (both presence and quantity) with CVD outcomes.MethodsThis single-center, retrospective study included women with a screening mammogram from 2007 to 2016. BAC was quantified using an artificial intelligence-generated score, which was assessed as both a binary and continuous variable. Regression analyses evaluated the association between BAC and mortality and a composite of acute myocardial infarction, heart failure, stroke, and mortality. Analyses were adjusted for age, race, diabetes, smoking, blood pressure, cholesterol, and history of CVD and chronic kidney disease.ResultsA total of 18,092 women were included in this study (mean age 56.8 ± 11.0 years; diabetes [13%], hypertension [36%], hyperlipidemia [40%], and smoking [5%]). BAC was present in 4,223 (23%). Over a median follow-up of 6 years, death occurred in 7.8% and 2.3% of women with and without BAC, respectively. The composite occurred in 12.4% and 4.3% of women with and without BAC, respectively. Compared to those without, women with BAC had adjusted HRs of 1.49 (95% CI: 1.33-1.67) for mortality and 1.56 (95% CI: 1.41-1.72) for the composite. Each 10-point increase in the BAC score was associated with higher risk of mortality (HR: 1.08 [95% CI: 1.06-1.11]) and the composite (HR: 1.08 [95% CI: 1.06-1.10]). BAC was especially predictive of future events among younger women.ConclusionsBAC is independently associated with mortality and CVD, especially among younger women. Measurement of BAC beyond presence adds incremental risk stratification. Quantifying BAC using an artificial intelligence algorithm is feasible, clinically relevant, and may improve personalized CVD risk stratification.

Adverse early life experiences are strongly associated with reduced cognitive function throughout life. The link is strong in many human studies, but these do not enable assigning causality, and the limited access to the live human brain can impede establishing the mechanisms by which early-life adversity (ELA) may induce cognitive problems. In experimental models, artificially imposed chronic ELA/stress results in deficits in hippocampus dependent memory as well as increased vulnerability to the deleterious effects of adult stress on memory. This causal relation of ELA and life-long memory impairments provides a framework to probe the mechanisms by which ELA may lead to human cognitive problems. Here we focus on the consequences of a one-week exposure to adversity during early postnatal life in the rodent, the spectrum of the ensuing memory deficits, and the mechanisms responsible. We highlight molecular, cellular and circuit mechanisms using convergent trans-disciplinary approaches aiming to enable translation of the discoveries in experimental models to the clinic.

IntroductionFew studies have examined the relationship between education and cognition among the oldest-old.MethodsCognitive assessments were conducted biannually for 803 participants (62.6% women) of LifeAfter90, a longitudinal study of individuals ≥ 90 years old. Gender differences in associations between education (

BACKGROUND: We aimed to develop risk tools for dementia, stroke, myocardial infarction (MI), and diabetes, for adults aged ≥ 65 years using shared risk factors. METHODS: Data were obtained from 10 population-based cohorts (N = 41,755) with median follow-up time (years) for dementia, stroke, MI, and diabetes of 6.2, 7.0, 6.8, and 7.4, respectively. Disease-free participants at baseline were included, and 22 risk factors (sociodemographic, medical, lifestyle, laboratory biomarkers) were evaluated. Two risk tools (DemNCD and DemNCD-LR based on Fine and Gray sub-distribution and logistic regression [LR], respectively) were developed and validated. Predictive accuracies of these risk tools were assessed using Harrels C-statistics and area under the curve (AUC) and 95% confidence interval (CI). Model calibration was conducted using Hosmer-Lemeshow goodness of fit test along calibration plots. RESULTS: Both the DemNCD and DemNCD-LR resulted in similar predictive accuracy for each outcome. The overall AUC (95% CI) for dementia, stroke, MI, and diabetes risk tool were 0·68 (0·65, 0·70), 0·58 (0·54, 0·61), 0·65 (0·61, 0·68), and 0·68 (0·64, 0·72), respectively, for males. For females, these figures were 0·65 (0·63, 0·67), 0·55 (0·52, 0·57), 0·65 (0·62, 0·68), and 0·61 (0·57, 0·65). CONCLUSIONS: The DemNCD is the first tool to predict both dementia and multiple cardio-metabolic diseases using comprehensive risk factors and provided similar predictive accuracy to existing risk tools. It has similar predictive accuracy as tools designed for single outcomes in this age-group. DemNCD has the potential to be used in community and clinical settings as it includes self-reported and routinely available clinical measures.

Background and hypothesisIt remains unclear whether the relation of chronic kidney disease (CKD) with cognitive dysfunction is independent of blood pressure (BP). We evaluated kidney function in relation to premorbid BP measurements, cerebral small vessel disease (CSVD), and incident mild cognitive impairment (MCI) and dementia in Framingham Offspring Cohort participants.MethodsWe included Framingham Offspring participants free of dementia, attending an examination during midlife (exam cycle 6, baseline) for ascertainment of kidney function status, with brain magnetic resonance imaging late in life (exam cycles 7-9), cognitive outcome data, and available interim hypertension and BP assessments. We related CKD (estimated glomerular filtration rate

The actin cytoskeleton is a key determinant of cell structure and homeostasis. However, possible tissue-specific changes to actin dynamics during aging, notably brain aging, are not understood. Here, we show that there is an age-related increase in filamentous actin (F-actin) in Drosophila brains, which is counteracted by prolongevity interventions. Critically, decreasing F-actin levels in aging neurons prevents age-onset cognitive decline and extends organismal healthspan. Mechanistically, we show that autophagy, a recycling process required for neuronal homeostasis, is disabled upon actin dysregulation in the aged brain. Remarkably, disrupting actin polymerization in aged animals with cytoskeletal drugs restores brain autophagy to youthful levels and reverses cellular hallmarks of brain aging. Finally, reducing F-actin levels in aging neurons slows brain aging and promotes healthspan in an autophagy-dependent manner. Our data identify excess actin polymerization as a hallmark of brain aging, which can be targeted to reverse brain aging phenotypes and prolong healthspan.

Subjective well-being (SWB) is often described as being U-shaped over adulthood, declining to a midlife slump and then improving thereafter. Improved SWB in later adulthood has been considered a paradox given age-related declines in health and social losses. While SWB has mostly been studied in high-income countries, it remains largely unexplored in rural subsistence populations lacking formal institutions that reliably promote social welfare. Here, we evaluate the age profile of SWB among three small-scale subsistence societies (n = 468; study 1), forest users from 23 low-income countries (n = 6987; study 2), and Tsimane horticulturalists (n = 1872; study 3). Across multiple specifications, we find variability in SWB age profiles. In some cases, we find no age-related differences in SWB or even inverted U-shapes. Adjusting for confounders reduces observed age effects. Our findings highlight variability in average well-being trajectories over the life course. Ensuring successful aging will require a greater focus on cultural and socioecological determinants of individual trajectories.

The Resource Centers for Minority Aging Research (RCMAR) is a flagship education, training, and development program of the National Institute of Health (NIH), and the National Institute on Aging (NIA) focused on increasing the number and diversity of researchers in aging. We sought to assess the program's contributions to geriatric and gerontology education by examining the scientific productivity of 294 RCMAR scientists who received pilot funding from the program during the last complete grant cycle, 2018 to 2023. Across the 18 funded sites, the scientists obtained 53 NIH grants and 29 NIA-specific grants. They published 281 manuscripts, of which 141 were noted as direct outcomes of the pilot funding and support received through the program. Findings indicated that the RCMAR program in its last cycle succeeded in promoting education and scientific career development of researchers from diverse backgrounds and researchers focused on health disparities to conduct transdisciplinary social and behavioral aging research.

Healthy aging is associated with structural and functional brain changes. However, cognitive abilities differ from one another in how they change with age: whereas executive functions, like working memory, show age-related decline, aspects of linguistic processing remain relatively preserved (Hartshorne et al., 2015). This heterogeneity of the cognitive-behavioral landscape in aging predicts differences among brain networks in whether and how they should change with age. To evaluate this prediction, we used individual-subject fMRI analyses ('precision fMRI') to examine the language-selective network (Fedorenko et al., 2024) and the Multiple Demand (MD) network, which supports executive functions (Duncan et al., 2020), in older adults (n=77) relative to young controls (n=470). In line with past claims, relative to young adults, the MD network of older adults shows weaker and less spatially extensive activations during an executive function task and reduced within-network functional synchronization. However, in stark contrast to the MD network, we find remarkable preservation of the language network in older adults. Their language network responds to language as strongly and selectively as in younger adults, and is similarly lateralized and internally synchronized. In other words, the language network of older adults looks indistinguishable from that of younger adults. Our findings align with behavioral preservation of language skills in aging and suggest that some networks remain young-like, at least on standard measures of function and connectivity.

Neuropsychiatric symptoms are common and disabling in Parkinson's disease (PD), with troublesome anxiety occurring in one-third of patients. Management of anxiety in PD is challenging, hampered by insufficient insight into underlying mechanisms, lack of objective anxiety measurements, and largely ineffective treatments. In this study, we assessed the intracranial neurophysiological correlates of anxiety in PD patients treated with deep brain stimulation (DBS) in the laboratory and at home. We hypothesized that low-frequency (theta-alpha) activity would be associated with anxiety. We recorded local field potentials (LFP) from the subthalamic nucleus (STN) or the globus pallidus pars interna (GPi) DBS implants in three PD cohorts: 1) patients with recordings (STN) performed in hospital at rest via perioperatively externalized leads, without active stimulation, both ON or OFF dopaminergic medication; 2) patients with recordings (STN or GPi) performed at home while resting, via a chronically implanted commercially available sensing-enabled neurostimulator (Medtronic PerceptTM device), ON dopaminergic medication, with stimulation both on or off; 3) patients with recordings performed at home while engaging in a behavioral task via STN and GPi leads and electrocorticography paddles over premotor cortex connected to an investigational sensing-enabled neurostimulator, ON dopaminergic medication, with stimulation both on or off. Trait anxiety was measured with validated clinical scales in all participants, and state anxiety was measured with momentary assessment scales at multiple time points in the two at-home cohorts. Power in theta (4-8 Hz) and alpha (8-12 Hz) ranges were extracted from the LFP recordings, and their relation with anxiety ratings was assessed using linear mixed-effects models. In total, 33 PD patients (59 hemispheres) were included. Across three independent cohorts, with stimulation off, basal ganglia theta power was positively related to trait anxiety (all p

IntroductionBlood-brain barrier (BBB) dysfunction occurs in Alzheimer's disease (AD). Yet, the stage at which it appears along the AD time course and whether it contributes to neurodegeneration remain unclear.MethodsOlder adults (61 to 90 years) from cognitively normal (CN) to mildly cognitively impaired (CI), enriched for APOE ?4 and amyloid positivity, underwent dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and diffusion MRI to measure BBB permeability and brain microstructure. Analysis of variance compared BBB permeability according to cognitive status, amyloid beta (Aβ), and APOE4. Linear regressions assessed associations of BBB permeability with brain microstructure and interactions with Aβ and APOE4.ResultsBBB permeability was elevated for APOE4 carriers across the cortical gray matter, with the strongest differences among CN amyloid-negative individuals. Associations between entorhinal BBB permeability and microstructure interacted with Aβ and APOE4, with the strongest relationships in amyloid-positive individuals and APOE4 carriers.DiscussionAPOE4 may drive widespread BBB dysfunction in preclinical AD, which may contribute to neurodegenerative changes early along the AD cascade.HighlightsGray matter blood-brain barrier (BBB) permeability is elevated for APOE4 carriers. APOE4-related BBB breakdown appears in the absence of cognitive decline or amyloid. BBB leakage correlates with entorhinal cortex microstructural injury. Associations with microstructure are strongest for amyloid-positive APOE4 carriers.

Early stages of Alzheimer's disease (AD) are associated with volume reductions in specific subregions of the medial temporal lobe (MTL). Using a manual segmentation method-the Olsen-Amaral-Palombo (OAP) protocol-previous work in healthy older adults showed that reductions in grey matter volumes in MTL subregions were associated with lower scores on the Montreal Cognitive Assessment (MoCA), suggesting atrophy may occur prior to diagnosis of mild cognitive impairment, a condition that often progresses to AD. However, current "gold standard" manual segmentation methods are labour intensive and time consuming. Here, we examined the utility of Automatic Segmentation of Hippocampal Subfields (ASHS) to detect volumetric differences in MTL subregions of healthy older adults who varied in cognitive status as determined by the MoCA. We trained ASHS on the OAP protocol to create the ASHS-OAP atlas and then examined how well automated segmentation replicated manual segmentation. Volumetric measures obtained from the ASHS-OAP atlas were also contrasted against those from the ASHS-PMC atlas, a widely used atlas provided by the ASHS team. The pattern of volumetric results was similar between the ASHS-OAP atlas and manual segmentation for anterolateral entorhinal cortex and perirhinal cortex, suggesting that ASHS-OAP is a viable alternative to current manual segmentation methods for detecting group differences based on cognitive status. Although ASHS-OAP and ASHS-PMC produced varying volumes for most regions of interest, they both identified early signs of neurodegeneration in CA2/CA3/DG and identified marginal differences in entorhinal cortex. Our findings highlight the utility of automated segmentation methods but still underscore the need for a unified and harmonized MTL segmentation atlas.

Protein aggregation is involved in many human diseases, but characterizing the sizes and shapes of intermediate oligomers (∼10-100 nm) that are important to the formation of macroscale aggregates like amyloid fibrils is a significant analytical challenge. Here, charge detection mass spectrometry (CDMS) is used to characterize individual conformational states of bovine serum albumin oligomers with up to ∼225 molecules (15 MDa). Elongated, partially folded, and globular conformational families for each oligomer can be readily distinguished based on the extent of charging. The abundances of individual conformers vary with changes in the monomer concentration or by adding aggregation inhibitors, such as SDS, heparin, or MgCl2. These results show the potential of CDMS for investigating intermediate oligomers in protein aggregation processes that are important for understanding aggregate formation and inhibition mechanisms and could accelerate formulation buffer development to prevent the aggregation of biotherapeutics.

Advances in antiretroviral therapy (ART) have made it possible for persons with human immunodeficiency virus (HIV) to live a lifespan approaching that of people without HIV, without progressing to AIDS or transmitting HIV to sexual partners or infants. There is, therefore, increasing emphasis on maintaining health throughout the lifespan. To receive optimal medical care and achieve desired outcomes, persons with HIV must be consistently engaged in care and able to access uninterrupted treatment, including ART. Comprehensive evidence-based HIV primary care guidance is, therefore, more important than ever. Creating a patient-centered, stigma-free care environment is essential for care engagement. Barriers to care must be decreased at the societal, health system, clinic, and individual levels. As the population ages and noncommunicable diseases arise, providing comprehensive health care for persons with HIV becomes increasingly complex, including management of multiple comorbidities and the associated challenges of polypharmacy, while also attending to HIV-specific health concerns. Clinicians must address issues specific to preventive health, including cancer screening, providing recommended vaccinations, as well as promoting sexual health, including sexually transmitted infection diagnosis, treatment, and prevention. Clinicians also must address issues for specific populations, including persons of childbearing potential, including during preconception and pregnancy; children; adolescents; and transgender and gender-diverse individuals. This guidance from an expert panel of the HIV Medicine Association of the Infectious Diseases Society of America updates the previous 2020 HIV Primary Care Guidance.

Study objectivesInsomnia symptoms are prevalent along the trajectory of Alzheimer's disease (AD), but the neurobiological underpinning of their interaction is poorly understood. Here, we assessed structural and functional brain measures within and between the default mode network (DMN), salience network, and central executive network (CEN).MethodsWe selected 320 participants from the ADNI database and divided them by their diagnosis: cognitively normal (CN), Mild Cognitive Impairment (MCI), and AD, with and without self-reported insomnia symptoms. We measured the gray matter volume (GMV), structural covariance (SC), degrees centrality (DC), and functional connectivity (FC), testing the effect and interaction of insomnia symptoms and diagnosis on each index. Subsequently, we performed a within-group linear regression across each network and ROI. Finally, we correlated observed abnormalities with changes in cognitive and affective scores.ResultsInsomnia symptoms were associated with FC alterations across all groups. The AD group also demonstrated an interaction between insomnia and diagnosis. Within-group analyses revealed that in CN and MCI, insomnia symptoms were characterized by within-network hyperconnectivity, while in AD, within- and between-network hypoconnectivity was ubiquitous. SC and GMV alterations were nonsignificant in the presence of insomnia symptoms, and DC indices only showed network-level alterations in the CEN of AD individuals. Abnormal FC within and between DMN and CEN hubs was additionally associated with reduced cognitive function across all groups, and increased depressive symptoms in AD.ConclusionsWe conclude that patients with clinical AD present with a unique pattern of insomnia-related functional alterations, highlighting the profound interaction between both conditions.

Pulmonary veno-occlusive disease (PVOD) is a rare but severe form of pulmonary hypertension characterized by the obstruction of pulmonary arteries and veins, causing increased pulmonary artery pressure and leading to right ventricular (RV) heart failure. PVOD is often resistant to conventional pulmonary arterial hypertension (PAH) treatments and has a poor prognosis, with a median survival time of 2-3 years after diagnosis. We previously showed that the administration of a chemotherapy agent mitomycin C (MMC) in rats mediates PVOD through the activation of the eukaryotic initiation factor 2 (eIF2) kinase protein kinase R (PKR) and the integrated stress response (ISR), resulting in the impairment of vascular endothelial junctional structure and barrier function. Here, we demonstrate that aged rats over 1 year exhibit more severe vascular remodeling and RV hypertrophy than young adult rats following MMC treatment. This is attributed to an age-associated elevation of basal ISR activity and depletion of protein phosphatase 1, leading to prolonged eIF2 phosphorylation and sustained ISR activation. Pharmacological blockade of PKR or ISR mitigates PVOD phenotypes in both age groups, suggesting that targeting the PKR/ISR axis could be a potential therapeutic strategy for PVOD.

Alterations in the nuclear envelope are linked to a variety of rare diseases termed laminopathies. A single amino acid substitution at position 12 (A12T) of the human nuclear envelope protein BAF (Barrier to Autointegration Factor) causes Néstor-Guillermo Progeria Syndrome (NGPS). This premature ageing condition leads to growth retardation and severe skeletal defects, but the underlying mechanisms are unknown. Here, we have generated a novel in vivo model for NGPS by modifying the baf-1 locus in C. elegans to mimic the human NGPS mutation. These baf-1(G12T) mutant worms displayed multiple phenotypes related to fertility, lifespan, and stress resistance. Importantly, nuclear morphology deteriorated faster during aging in baf-1(G12T) compared to wild-type animals, recapitulating an important hallmark of cells from progeria patients. Although localization of BAF-1(G12T) was similar to wild-type BAF-1, lamin accumulation at the nuclear envelope was reduced in mutant worms. Tissue-specific chromatin binding and transcriptome analyses showed reduced BAF-1 association in most genes deregulated by the baf-1(G12T) mutation, suggesting that altered BAF chromatin association induces NGPS phenotypes via altered gene expression.

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample size. These efforts unveil new questions about how to integrate data across distinct sources and instruments. The goal of this study was to link scores across common auditory verbal learning tasks (AVLTs). This international secondary analysis aggregated multisite raw data for AVLTs across 53 studies totaling 10,505 individuals. Using the ComBat-GAM algorithm, we isolated and removed the component of memory scores associated with site effects while preserving instrumental effects. After adjustment, a continuous item response theory model used multiple memory items of varying difficulty to estimate each individual's latent verbal learning ability on a single scale. Equivalent raw scores across AVLTs were then found by linking individuals through the ability scale. Harmonization reduced total cross-site score variance by 37% while preserving meaningful memory effects. Age had the largest impact on scores overall (- 11.4%), while race/ethnicity variable was not significant (p > 0.05). The resulting tools were validated on dually administered tests. The conversion tool is available online so researchers and clinicians can convert memory scores across instruments. This work demonstrates that global harmonization initiatives can address reproducibility challenges across the behavioral sciences.

Industrialized environments, despite benefits such as higher levels of formal education and lower rates of infections, can also have pernicious impacts upon brain atrophy. Partly for this reason, comparing age-related brain volume trajectories between industrialized and non-industrialized populations can help to suggest lifestyle correlates of brain health. The Tsimane, indigenous to the Bolivian Amazon, derive their subsistence from foraging and horticulture and are physically active. The Moseten, a mixed-ethnicity farming population, are physically active but less than the Tsimane. Within both populations (N = 1024; age range = 46-83), we calculated regional brain volumes from computed tomography and compared their cross-sectional trends with age to those of UK Biobank (UKBB) participants (N = 19,973; same age range). Surprisingly among Tsimane and Moseten (T/M) males, some parietal and occipital structures mediating visuospatial abilities exhibit small but significant increases in regional volume with age. UKBB males exhibit a steeper negative trend of regional volume with age in frontal and temporal structures compared to T/M males. However, T/M females exhibit significantly steeper rates of brain volume decrease with age compared to UKBB females, particularly for some cerebro-cortical structures (e.g., left subparietal cortex). Across the three populations, observed trends exhibit no interhemispheric asymmetry. In conclusion, the age-related rate of regional brain volume change may differ by lifestyle and sex. The lack of brain volume reduction with age is not known to exist in other human population, highlighting the putative role of lifestyle in constraining regional brain atrophy and promoting elements of non-industrialized lifestyle like higher physical activity.

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.

Type 2 diabetes mellitus (T2DM) increases the risk of neurological diseases, yet how brain oscillations change as age and T2DM interact is not well characterized. To delineate the age and diabetic effect on neurophysiology, we recorded local field potentials with multichannel electrodes spanning the somatosensory cortex and hippocampus (HPC) under urethane anesthesia in diabetic and normoglycemic control mice, at 200 and 400 days of age. We analyzed the signal power of brain oscillations, brain state, sharp wave associate ripples (SPW-Rs), and functional connectivity between the cortex and HPC. We found that while both age and T2DM were correlated with a breakdown in long-range functional connectivity and reduced neurogenesis in the dentate gyrus and subventricular zone, T2DM further slowed brain oscillations and reduced theta-gamma coupling. Age and T2DM also prolonged the duration of SPW-Rs and increased gamma power during SPW-R phase. Our results have identified potential electrophysiological substrates of hippocampal changes associated with T2DM and age. The perturbed brain oscillation features and diminished neurogenesis may underlie T2DM-accelerated cognitive impairment.

Brain aging process is influenced by various lifestyle, environmental and genetic factors, as well as by age-related and often coexisting pathologies. Magnetic resonance imaging and artificial intelligence methods have been instrumental in understanding neuroanatomical changes that occur during aging. Large, diverse population studies enable identifying comprehensive and representative brain change patterns resulting from distinct but overlapping pathological and biological factors, revealing intersections and heterogeneity in affected brain regions and clinical phenotypes. Herein, we leverage a state-of-the-art deep-representation learning method, Surreal-GAN, and present methodological advances and extensive experimental results elucidating brain aging heterogeneity in a cohort of 49,482 individuals from 11 studies. Five dominant patterns of brain atrophy were identified and quantified for each individual by respective measures, R-indices. Their associations with biomedical, lifestyle and genetic factors provide insights into the etiology of observed variances, suggesting their potential as brain endophenotypes for genetic and lifestyle risks. Furthermore, baseline R-indices predict disease progression and mortality, capturing early changes as supplementary prognostic markers. These R-indices establish a dimensional approach to measuring aging trajectories and related brain changes. They hold promise for precise diagnostics, especially at preclinical stages, facilitating personalized patient management and targeted clinical trial recruitment based on specific brain endophenotypic expression and prognosis.

The magnetic resonance imaging (MRI) Core has been operating since Alzheimer's Disease Neuroimaging Initiative's (ADNI) inception, providing 20 years of data including reliable, multi-platform standardized protocols, carefully curated image data, and quantitative measures provided by expert investigators. The overarching purposes of the MRI Core include: (1) optimizing and standardizing MRI acquisition methods, which have been adopted by many multicenter studies and trials worldwide and (2) providing curated images and numeric summary values from relevant MRI sequences/contrasts to the scientific community. Over time, ADNI MRI has become increasingly complex. To remain technically current, the ADNI MRI protocol has changed substantially over the past two decades. The ADNI 4 protocol contains nine different imaging types (e.g., three dimensional [3D] T1-weighted and fluid-attenuated inversion recovery [FLAIR]). Our view is that the ADNI MRI data are a greatly underutilized resource. The purpose of this paper is to educate the scientific community on ADNI MRI methods and content to promote greater awareness, accessibility, and use. HIGHLIGHTS: The MRI Core provides multi-platform standardized protocols, carefully curated image data, and quantitative analysis by expert groups. The ADNI MRI protocol has undergone major changes over the past two decades to remain technically current. As of April 25, 2024, the following numbers of image series are available: 17,141 3D T1w; 6877 FLAIR; 3140 T2/PD; 6623 GRE; 3237 dMRI; 2846 ASL; 2968 TF-fMRI; and 2861 HighResHippo (see Table 1 for abbreviations). As of April 25, 2024, the following numbers of quantitative analyses are available: FreeSurfer 10,997; BSI 6120; tensor based morphometry (TBM) and TBM-SYN 12,019; WMH 9944; dMRI 1913; ASL 925; TF-fMRI NFQ 2992; and medial temporal subregion volumes 2726 (see Table 4 for abbreviations). ADNI MRI is an underutilized resource that could be more useful to the research community.

BackgroundDigital cognitive assessments, particularly those that can be done at home, present as low-burden biomarkers for participants and patients alike, but their effectiveness in the diagnosis of Alzheimer's disease (AD) or predicting its trajectory is still unclear. Here, we assessed what utility or added value these digital cognitive assessments provide for identifying those at high risk of cognitive decline.MethodsWe analyzed >500 Alzheimer's Disease Neuroimaging Initiative participants who underwent a brief digital cognitive assessment and amyloid beta (Aβ)/tau positron emission tomography scans, examining their ability to distinguish cognitive status and predict cognitive decline.ResultsPerformance on the digital cognitive assessment was superior to both cortical Aβ and entorhinal tau in detecting mild cognitive impairment and future cognitive decline, with mnemonic discrimination deficits emerging as the most critical measure for predicting decline and future tau accumulation.DiscussionDigital assessments are effective at identifying at-risk individuals, supporting their utility as low-burden tools for early AD detection and monitoring.HighlightsPerformance on digital cognitive assessments predicts progression to mild cognitive impairment at a higher proficiency compared to amyloid beta and tau. Deficits in mnemonic discrimination are indicative of future cognitive decline. Impaired mnemonic discrimination predicts future entorhinal and inferior temporal tau.