Advanced Brain Aging Research Articles

Exploring associations between psychotic experiences and structural brain age: a population-based study in late adolescence.

Neuroimaging studies show advanced structural "brain age" in schizophrenia and related psychotic disorders, potentially reflecting aberrant brain ageing or maturation. The extent to which altered brain age is associated with subthreshold psychotic experiences (PE) in youth remains unclear. We investigated the association between PE and brain-predicted age difference (brain-PAD) in late adolescence using a population-based sample of 117 participants with PE and 115 without PE (aged 19-21 years) from the Avon Longitudinal Study of Parents and Children. Brain-PAD was estimated using a publicly available machine learning model previously trained on a combination of region-wise T1-weighted grey-matter measures. We found little evidence for an association between PEs and brain-PAD after adjusting for age and sex (Cohen's d = -0.21 [95% CI -0.47, 0.05], p = 0.11). While there was some evidence for lower brain-PAD in those with PEs relative to those without PEs after additionally adjusting for parental social class (Cohen's d = -0.31 [95% CI -0.58, -0.03], p = 0.031) or birth weight (Cohen's d = -0.29 [95% CI -0.55, -0.03], p = 0.038), adjusting for maternal education or childhood IQ did not alter the primary results. These findings do not support the notion of advanced brain age in older adolescents with PEs. However, they weakly suggest there might be a younger-looking brain in those individuals, indicative of subtle delays in structural brain maturation. Future studies with larger samples covering a wider age range and multimodal measures could further investigate brain age as a marker of psychotic experiences in youth.

Alzheimer's disease genetic risk and changes in brain atrophy and white matter hyperintensities in cognitively unimpaired adults.

Reduced brain volumes and more prominent white matter hyperintensities on MRI scans are commonly observed among older adults without cognitive impairment. However, it remains unclear whether rates of change in these measures among cognitively normal adults differ as a function of genetic risk for late-onset Alzheimer's disease, including APOE-ɛ4, APOE-ɛ2 and Alzheimer's disease polygenic risk scores (AD-PRS), and whether these relationships are influenced by other variables. This longitudinal study examined the trajectories of regional brain volumes and white matter hyperintensities in relationship to APOE genotypes (N = 1541) and AD-PRS (N = 1093) in a harmonized dataset of middle-aged and older individuals with normal cognition at baseline (mean baseline age = 66 years, SD = 9.6) and an average of 5.3 years of MRI follow-up (max = 24 years). Atrophy on volumetric MRI scans was quantified in three ways: (i) a composite score of regions vulnerable to Alzheimer's disease (SPARE-AD); (ii) hippocampal volume; and (iii) a composite score of regions indexing advanced non-Alzheimer's disease-related brain aging (SPARE-BA). Global white matter hyperintensity volumes were derived from fluid attenuated inversion recovery (FLAIR) MRI. Using linear mixed effects models, there was an APOE-ɛ4 gene-dose effect on atrophy in the SPARE-AD composite and hippocampus, with greatest atrophy among ɛ4/ɛ4 carriers, followed by ɛ4 heterozygouts, and lowest among ɛ3 homozygouts and ɛ2/ɛ2 and ɛ2/ɛ3 carriers, who did not differ from one another. The negative associations of APOE-ɛ4 with atrophy were reduced among those with higher education (P < 0.04) and younger baseline ages (P < 0.03). Higher AD-PRS were also associated with greater atrophy in SPARE-AD (P = 0.035) and the hippocampus (P = 0.014), independent of APOE-ɛ4 status. APOE-ɛ2 status (ɛ2/ɛ2 and ɛ2/ɛ3 combined) was not related to baseline levels or atrophy in SPARE-AD, SPARE-BA or the hippocampus, but was related to greater increases in white matter hyperintensities (P = 0.014). Additionally, there was an APOE-ɛ4 × AD-PRS interaction in relation to white matter hyperintensities (P = 0.038), with greater increases in white matter hyperintensities among APOE-ɛ4 carriers with higher AD-PRS. APOE and AD-PRS associations with MRI measures did not differ by sex. These results suggest that APOE-ɛ4 and AD-PRS independently and additively influence longitudinal declines in brain volumes sensitive to Alzheimer's disease and synergistically increase white matter hyperintensity accumulation among cognitively normal individuals. Conversely, APOE-ɛ2 primarily influences white matter hyperintensity accumulation, not brain atrophy. Results are consistent with the view that genetic factors for Alzheimer's disease influence atrophy in a regionally specific manner, likely reflecting preclinical neurodegeneration, and that Alzheimer's disease risk genes contribute to white matter hyperintensity formation.

Clinical and multimodal imaging features of adult-onset neuronal intranuclear inclusion disease.

This study aimed to analyze the clinical and multimodal imaging manifestations of adult-onset neuronal intranuclear inclusion disease (NIID) patients and to investigate NIID-specific neuroimaging biomarkers. Forty patients were retrospectively enrolled from the Qilu Hospital of Shandong University. We analyzed the clinical and imaging characteristics of 40 adult-onset NIID patients and investigated the correlation between these characteristics and genetic markers and neuropsychological scores. We further explored NIID-specific alterations using multimodal imaging indices, including diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), and brain age estimation. In addition, we summarized the dynamic evolution pattern of NIID by examining the changes in diffusion weighted imaging (DWI) signals over time. The NIID patients' ages ranged from 31 to 77 years. Cognitive impairment was the most common symptom (30/40, 75.0%), while some patients (18/40, 45.0%) initially presented with episodic symptoms such as headache (10/40, 25.0%). Patients with cognitive impairment symptoms had more cerebral white matter damage (χ2 = 11.475, P = 0.009). The most prevalent imaging manifestation was a high signal on DWI in the corticomedullary junction area, which was observed in 80.0% (32/40) of patients. In addition, the DWI dynamic evolution patterns could be classified into four main patterns. Diffusion tensor imaging (DTI) revealed extensive thinning of cerebral white matter fibers. The estimated brain age surpassed the patient's chronological age, signifying advanced brain aging in NIID patients. The clinical manifestations of NIID exhibit significant variability, usually leading to misdiagnosis. Our results provided new imaging perspectives for accurately diagnosing and exploring this disease's neuropathological mechanisms.

Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi-Cohort Mega-Analysis.

The long-term consequences of traumatic brain injury (TBI) on brain structure remain uncertain. Given evidence that a single significant brain injury event increases the risk of dementia, brain-age estimation could provide a novel and efficient indexing of the long-term consequences of TBI. Brain-age procedures use predictive modeling to calculate brain-age scores for an individual using structural magnetic resonance imaging (MRI) data. Complicated mild, moderate, and severe TBI (cmsTBI) is associated with a higher predicted age difference (PAD), but the progression of PAD over time remains unclear. We sought to examine whether PAD increases as a function of time since injury (TSI) and if injury severity and sex interacted to influence this progression. Through the ENIGMA Adult Moderate and Severe (AMS)-TBI working group, we examine the largest TBI sample to date (n = 343), along with controls, for a total sample size of n = 540, to replicate and extend prior findings in the study of TBI brain age. Cross-sectional T1w-MRI data were aggregated across 7 cohorts, and brain age was established using a similar brain age algorithm to prior work in TBI. Findings show that PAD widens with longer TSI, and there was evidence for differences between sexes in PAD, with men showing more advanced brain age. We did not find strong evidence supporting a link between PAD and cognitive performance. This work provides evidence that changes in brain structure after cmsTBI are dynamic, with an initial period of change, followed by relative stability in brain morphometry, eventually leading to further changes in the decades after a single cmsTBI. ANN NEUROL 2024;96:365-377.

Multiscale brain age prediction reveals region-specific accelerated brain aging in Parkinson's disease

Brain biological age, which measures the aging process in the brain using neuroimaging data, has been used to assess advanced brain aging in neurodegenerative diseases, including Parkinson disease (PD). However, assuming that whole brain degeneration is uniform may not be sufficient for assessing the complex neurodegenerative processes in PD. In this study we constructed a multiscale brain age prediction models based on structural MRI of 1240 healthy participants. To assess the brain aging patterns using the brain age prediction model, 93 PD patients and 91 healthy controls matching for sex and age were included. We found increased global and regional brain age in PD patients. The advanced aging regions were predominantly noted in the frontal and temporal cortices, limbic system, basal ganglia, thalamus, and cerebellum. Furthermore, region-level rather than global brain age in PD patients was associated with disease severity. Our multiscale brain age prediction model could aid in the development of objective image-based biomarkers to detect advanced brain aging in neurodegenerative diseases.

The effect of head motion on brain age prediction using deep convolutional neural networks

Deep learning can be used effectively to predict participants' age from brain magnetic resonance imaging (MRI) data, and a growing body of evidence suggests that the difference between predicted and chronological age—referred to as brain-predicted age difference (brain-PAD)—is related to various neurological and neuropsychiatric disease states. A crucial aspect of the applicability of brain-PAD as a biomarker of individual brain health is whether and how brain-predicted age is affected by MR image artifacts commonly encountered in clinical settings. To investigate this issue, we trained and validated two different 3D convolutional neural network architectures (CNNs) from scratch and tested the models on a separate dataset consisting of motion-free and motion-corrupted T1-weighted MRI scans from the same participants, the quality of which were rated by neuroradiologists from a clinical diagnostic point of view. Our results revealed a systematic increase in brain-PAD with worsening image quality for both models. This effect was also observed for images that were deemed usable from a clinical perspective, with brains appearing older in medium than in good quality images. These findings were also supported by significant associations found between the brain-PAD and standard image quality metrics indicating larger brain-PAD for lower-quality images. Our results demonstrate a spurious effect of advanced brain aging as a result of head motion and underline the importance of controlling for image quality when using brain-predicted age based on structural neuroimaging data as a proxy measure for brain health.

Advanced brain aging in Parkinson’s disease with cognitive impairment

Patients with Parkinson’s disease and cognitive impairment (PD-CI) deteriorate faster than those without cognitive impairment (PD-NCI), suggesting an underlying difference in the neurodegeneration process. We aimed to verify brain age differences in PD-CI and PD-NCI and their clinical significance. A total of 94 participants (PD-CI, n = 27; PD-NCI, n = 34; controls, n = 33) were recruited. Predicted age difference (PAD) based on gray matter (GM) and white matter (WM) features were estimated to represent the degree of brain aging. Patients with PD-CI showed greater GM-PAD (7.08 ± 6.64 years) and WM-PAD (8.82 ± 7.69 years) than those with PD-NCI (GM: 1.97 ± 7.13, Padjusted = 0.011; WM: 4.87 ± 7.88, Padjusted = 0.049) and controls (GM: -0.58 ± 7.04, Padjusted = 0.004; WM: 0.88 ± 7.45, Padjusted = 0.002) after adjusting demographic factors. In patients with PD, GM-PAD was negatively correlated with MMSE (Padjusted = 0.011) and MoCA (Padjusted = 0.013) and positively correlated with UPDRS Part II (Padjusted = 0.036). WM-PAD was negatively correlated with logical memory of immediate and delayed recalls (Padjusted = 0.003 and Padjusted < 0.001). Also, altered brain regions in PD-CI were identified and significantly correlated with brain age measures, implicating the neuroanatomical underpinning of neurodegeneration in PD-CI. Moreover, the brain age metrics can improve the classification between PD-CI and PD-NCI. The findings suggest that patients with PD-CI had advanced brain aging that was associated with poor cognitive functions. The identified neuroimaging features and brain age measures can serve as potential biomarkers of PD-CI.

Brain Age Prediction Based on Quantitative Susceptibility Mapping Using the Segmentation Transformer.

The process of brain aging is intricate, encompassing significant structural and functional changes, including myelination and iron deposition in the brain. Brain age could act as a quantitative marker to evaluate the degree of the individual's brain evolution. Quantitative susceptibility mapping (QSM) is sensitive to variations in magnetically responsive substances such as iron and myelin, making it a favorable tool for estimating brain age. In this study, we introduce an innovative 3D convolutional network named Segmentation-Transformer-Age-Network (STAN) to predict brain age based on QSM data. STAN employs a two-stage network architecture. The first-stage network learns to extract informative features from the QSM data through segmentation training, while the second-stage network predicts brain age by integrating the global and local features. We collected QSM images from 712 healthy participants, with 548 for training and 164 for testing. The results demonstrate that the proposed method achieved a high accuracy brain age prediction with a mean absolute error (MAE) of 4.124 years and a coefficient of determination (R2) of 0.933. Furthermore, the gaps between the predicted brain age and the chronological age of Parkinson's disease patients were significantly higher than those of healthy subjects (P<0.01). We thus believe that using QSM-based predicted brain age offers a more reliable and accurate phenotype, with the potentiality to serve as a biomarker to explore the process of advanced brain aging.

Deep Learning-based Brain Age Prediction in Patients With Schizophrenia Spectrum Disorders.

The brain-predicted age difference (brain-PAD) may serve as a biomarker for neurodegeneration. We investigated the brain-PAD in patients with schizophrenia (SCZ), first-episode schizophrenia spectrum disorders (FE-SSDs), and treatment-resistant schizophrenia (TRS) using structural magnetic resonance imaging (sMRI). We employed a convolutional network-based regression (SFCNR), and compared its performance with models based on three machine learning (ML) algorithms. We pretrained the SFCNR with sMRI data of 7590 healthy controls (HCs) selected from the UK Biobank. The parameters of the pretrained model were transferred to the next training phase with a new set of HCs (n = 541). The brain-PAD was analyzed in independent HCs (n = 209) and patients (n = 233). Correlations between the brain-PAD and clinical measures were investigated. The SFCNR model outperformed three commonly used ML models. Advanced brain aging was observed in patients with SCZ, FE-SSDs, and TRS compared to HCs. A significant difference in brain-PAD was observed between FE-SSDs and TRS with ridge regression but not with the SFCNR model. Chlorpromazine equivalent dose and cognitive function were correlated with the brain-PAD in SCZ and FE-SSDs. Our findings indicate that there is advanced brain aging in patients with SCZ and higher brain-PAD in SCZ can be used as a surrogate marker for cognitive dysfunction. These findings warrant further investigations on the causes of advanced brain age in SCZ. In addition, possible psychosocial and pharmacological interventions targeting brain health should be considered in early-stage SCZ patients with advanced brain age.

Assessing the association between global structural brain age and polygenic risk for schizophrenia in early adulthood: A recall-by-genotype study

Neuroimaging studies consistently show advanced brain age in schizophrenia, suggesting that brain structure is often ‘older’ than expected at a given chronological age. Whether advanced brain age is linked to genetic liability for schizophrenia remains unclear. In this pre-registered secondary data analysis, we utilised a recall-by-genotype approach applied to a population-based subsample from the Avon Longitudinal Study of Parents and Children to assess brain age differences between young adults aged 21–24 years with relatively high (n = 96) and low (n = 93) polygenic risk for schizophrenia (SCZ-PRS). A global index of brain age (or brain-predicted age) was estimated using a publicly available machine learning model previously trained on a combination of region-wise gray-matter measures, including cortical thickness, surface area and subcortical volumes derived from T1-weighted magnetic resonance imaging (MRI) scans. We found no difference in mean brain-PAD (the difference between brain-predicted age and chronological age) between the high- and low-SCZ-PRS groups, controlling for the effects of sex and age at time of scanning (b = −.21; 95% CI −2.00, 1.58; p = .82; Cohen's d = −.034; partial R2 = .00029). These findings do not support an association between SCZ-PRS and brain-PAD based on global age-related structural brain patterns, suggesting that brain age may not be a vulnerability marker of common genetic risk for SCZ. Future studies with larger samples and multimodal brain age measures could further investigate global or localised effects of SCZ-PRS.

Chicken vs. Egg? A Lifespan Perspective on Education and IQ in Cognitive Reserve Research

AbstractBackgroundInferences about cognitive reserve and related constructs may be subject to reverse causation, but too often the possibility of reverse causation is not addressed in research on reserve and resilience. A lifespan perspective can shed light on the relationships among education, IQ, and related constructs and what can be concluded about causality with respect to late‐life cognitive and dementia outcomes.MethodWe use general cognitive ability (GCA) to refer to IQ or IQ‐like measures. We provide examples from the literature plus some new findings examining the effect of cognitive reserve on late‐life outcomes and how modifiable factors may impact reserve and resilience effects. Some of the data presented are from genetically‐informative studies that help to clarify issues related to causality.ResultThere is a bidirectional relationship between education and GCA, but the directional influences change across the lifespan. The relationship is not unidirectional in childhood and adolescence, but during that period more education does increase GCA. The effect reaches an asymptote, and in late adolescence and early adulthood, the causal direction shifts toward GCA driving educational attainment. When both education and GCA are in the same model, both longitudinal phenotypic and Mendelian randomization studies show that GCA is a stronger driver of late‐life cognitive and dementia outcomes than education. Appropriately designed studies often support the idea that occupational complexity and engagement in enriching activities are not directly causal, but are downstream effects of GCA. Finally, earlier lifestyle factors can moderate associations between cognitive reserve and late‐life outcomes. For example, favorable early midlife social/health behaviors can offset advanced brain aging in individuals with lower cognitive reserve (i.e., lower young adult GCA).ConclusionThe results have implications regarding interventions to improve cognitive reserve and resilience, and what the balance should be when it comes to resources for early‐ versus late‐life interventions. The primary direction of causal effects raises questions about how and, importantly, when during the lifespan, increased education, cognitive enrichment/training programs (which may be thought of as a type of education), or other lifestyle factors are likely to increase reserve or resilience, thereby improving cognitive function and reducing dementia risk.

Elevated Pure Tone Thresholds Are Associated with Altered Microstructure in Cortical Areas Related to Auditory Processing and Attentional Allocation.

Hearing loss is associated with cognitive decline and increased risk for Alzheimer's disease, but the basis of this association is not understood. To determine whether hearing impairment is associated with advanced brain aging or altered microstructure in areas involved with auditory and cognitive processing. 130 participants, (mean 76.4±7.3 years; 65% women) of the Rancho Bernardo Study of Healthy Aging had a screening audiogram in 2003-2005 and brain magnetic resonance imaging in 2014-2016. Hearing ability was defined as the average pure tone threshold (PTA) at 500, 1000, 2000, and 4000 Hz in the better-hearing ear. Brain-predicted age difference (Brain-pad) was calculated as the difference between brain-predicted age based on a validated structural imaging biomarker of brain age, and chronological age. Regional diffusion metrics in temporal and frontal cortex regions were obtained from diffusion-weighted MRIs. Linear regression analyses adjusted for age, gender, education, and health-related measures. PTAs were not associated with brain-PAD (β= 0.09; 95% CI: -0.084 to 0.243; p = 0.34). PTAs were associated with reduced restricted diffusion and increased free water diffusion primarily in right hemisphere temporal and frontal areas (restricted diffusion: βs = -0.21 to -0.30; 95% CIs from -0.48 to -0.02; ps < 0.03; free water: βs = 0.18 to 0.26; 95% CIs 0.01 to 0.438; ps < 0.04). Hearing impairment is not associated with advanced brain aging but is associated with differences in brain regions involved with auditory processing and attentional control. It is thus possible that increased dementia risk associated with hearing impairment arises, in part, from compensatory brain changes that may decrease resilience.

Association Between Psychosocial Stress and Brain Aging: Results of the Population-Based Cohort Study of Health in Pomerania (SHIP).

Recent studies suggest that psychosocial factors can have an impact on brain health. Yet, it is unclear whether psychosocial stress affects aging of the brain. The aim of the study was to investigate the association between psychosocial stress and brain aging. Data from the German population-based cohort Study of Health in Pomerania (N=991; age range 20-78 years) were used to calculate a total psychosocial stress score by combining subscores from five domains: stress related to the living situation, the occupational situation, the social situation, danger experiences, and emotions. Associations with brain aging, indicated by an MRI-derived score quantifying age-related brain atrophy, were estimated by using regression models adjusted for age, gender, education, diabetes, problematic alcohol consumption, smoking, and hypertension. The relative risk ratio for advanced brain aging was 1.21 (95% CI=1.04-1.41) for stress related to emotions in fully adjusted models. The interactions between stress related to emotions and mental health symptoms were also significantly associated with advanced brain aging. The association between higher total psychosocial stress and brain aging was not statistically significant. These findings highlight that high stress related to emotions is associated with advanced brain aging. To protect brain health in older age, more research is needed to explore the role of emotional distress.

Dynamic network properties of the superior temporal gyrus mediate the impact of brain age gap on chronic aphasia severity

Brain structure deteriorates with aging and predisposes an individual to more severe language impairments (aphasia) after a stroke. However, the underlying mechanisms of this relation are not well understood. Here we use an approach to model brain network properties outside the stroke lesion, network controllability, to investigate relations among individualized structural brain connections, brain age, and aphasia severity in 93 participants with chronic post-stroke aphasia. Controlling for the stroke lesion size, we observe that lower average controllability of the posterior superior temporal gyrus (STG) mediates the relation between advanced brain aging and aphasia severity. Lower controllability of the left posterior STG signifies that activity in the left posterior STG is less likely to yield a response in other brain regions due to the topological properties of the structural brain networks. These results indicate that advanced brain aging among individuals with post-stroke aphasia is associated with disruption of dynamic properties of a critical language-related area, the STG, which contributes to worse aphasic symptoms. Because brain aging is variable among individuals with aphasia, our results provide further insight into the mechanisms underlying the variance in clinical trajectories in post-stroke aphasia.

Advanced brain age in community-dwelling population with combined physical and cognitive impairments

We investigated whether advanced brain biological age is associated with accelerated age-related physical and/or cognitive functional decline: mobility impairment no disability (MIND), cognitive impairment no dementia (CIND), and physio-cognitive decline syndrome (PCDS). We constructed a brain age prediction model using gray matter features from the magnetic resonance imaging of 1482 healthy individuals (aged 18–92 years). Predicted and chronological age differences were obtained (brain age gap [BAG]) and analyzed in another 1193 community-dwelling population aged ≥50 years. Among the 1193 participants, there were 501, 346, 148, and 198 in the robust, CIND, MIND, and PCDS groups, respectively. Participants with PCDS had significantly larger BAG (BAG = 2.99 ± 8.97) than the robust (BAG = −0.49 ± 9.27, p = 0.002; η2 = 0.014), CIND (BAG = 0.47 ± 9.16, p = 0.02; η2 = 0.01), and MIND (BAG = 0.36 ± 9.69, p = 0.036; η2 = 0.013) groups. Advanced brain aging is involved in the pathophysiology of the co-occurrence of physical and cognitive decline in the older people. The PCDS may be a clinical phenotype reflective of accelerated biological age in community-dwelling older individuals.

"Brain age" predicts disability accumulation in multiple sclerosis.

Neurodegenerative conditions often manifest radiologically with the appearance of premature aging. Multiple sclerosis (MS) biomarkers related to lesion burden are well developed, but measures of neurodegeneration are less well-developed. The appearance of premature aging quantified by machine learning applied to structural MRI assesses neurodegenerative pathology. We assess the explanatory and predictive power of "brain age" analysis on disability in MS using a large, real-world dataset. Brain age analysis is predicated on the over-estimation of predicted brain age in patients with more advanced pathology. We compared the performance of three brain age algorithms in a large, longitudinal dataset (>13,000 imaging sessions from >6,000 individual MS patients). Effects of MS, MS disease course, disability, lesion burden, and DMT efficacy were assessed using linear mixed effects models. MS was associated with advanced predicted brain age cross-sectionally and accelerated brain aging longitudinally in all techniques. While MS disease course (relapsing vs. progressive) did contribute to advanced brain age, disability was the primary correlate of advanced brain age. We found that advanced brain age at study enrollment predicted more disability accumulation longitudinally. Lastly, a more youthful appearing brain (predicted brain age less than actual age) was associated with decreased disability. Brain age is a technically tractable and clinically relevant biomarker of disease pathology that correlates with and predicts increasing disability in MS. Advanced brain age predicts future disability accumulation.

Isolated catatonia-like executive dysfunction in mice with forebrain-specific loss of myelin integrity.

A key feature of advanced brain aging includes structural defects of intracortical myelin that are associated with secondary neuroinflammation. A similar pathology is seen in specific myelin mutant mice that model 'advanced brain aging' and exhibit a range of behavioral abnormalities. However, the cognitive assessment of these mutants is problematic because myelin-dependent motor-sensory functions are required for quantitative behavioral readouts. To better understand the role of cortical myelin integrity for higher brain functions, we generated mice lacking Plp1, encoding the major integral myelin membrane protein, selectively in ventricular zone stem cells of the mouse forebrain. In contrast to conventional Plp1 null mutants, subtle myelin defects were restricted to the cortex, hippocampus, and underlying callosal tracts. Moreover, forebrain-specific Plp1 mutants exhibited no defects of basic motor-sensory performance at any age tested. Surprisingly, several behavioral alterations reported for conventional Plp1 null mice (Gould et al., 2018) were absent and even social interactions appeared normal. However, with novel behavioral paradigms, we determined catatonia-like symptoms and isolated executive dysfunction in both genders. This suggests that loss of myelin integrity has an impact on cortical connectivity and underlies specific defects of executive function. These observations are likewise relevant for human neuropsychiatric conditions and other myelin-related diseases.

Neuroimaging-Derived Predicted Brain Age and Alcohol Use Among Community-Dwelling Older Adults

ObjectivesObservational studies have suggested that moderate alcohol use is associated with reduced risk of dementia. However, the nature of this association is not understood. We investigated whether light to moderate alcohol use may be associated with slower brain aging, among a cohort of older community-dwelling adults using a biomarker of brain age based on structural neuroimaging measures. DesignCross-sectional observational study. ParticipantsWell-characterized members of a longitudinal cohort study who underwent neuroimaging. We categorized the 163 participants (mean age 76.7 ± 7.7, 60% women) into current nondrinkers, light drinkers (1–7 drinks/week) moderate drinkers (>7–14 drinks/week), or heavier drinkers (>14 drinks/week). MeasurementsWe calculated brain-predicted age using structural MRIs processed with the BrainAgeR program, and calculated the difference between brain-predicted age and chronological age (brain-predicted age difference, or brain-PAD). We used analysis of variance to determine if brain-PAD differed across alcohol groups, controlling for potential confounders. ResultsBrain-PAD differed across alcohol groups (F[3, 150] = 4.02; p = 0.009) with heavier drinkers showing older brain-PAD than light drinkers (by about 6 years). Brain-PAD did not differ across light, moderate, and nondrinkers. Similar results were obtained after adjusting for potentially mediating health-related measures, and after excluding individuals with a history of heavier drinking. DiscussionAmong this sample of healthy older adults, consumption of more than 14 drinks/week was associated with a biomarker of advanced brain aging. Light and moderate drinking was not associated with slower brain aging relative to non-drinking.

AAGP Session to Highlight Research on Resilience, Emotional Well-Being in Aging

AAGP Session to Highlight Research on Resilience, Emotional Well-Being in Aging

Health-related heterogeneity in brain aging and associations with longitudinal change in cognitive function.

Neuroimaging-based 'brain age' can identify individuals with 'advanced' or 'resilient' brain aging. Brain-predicted age difference (brain-PAD) is predictive of cognitive and physical health outcomes. However, it is unknown how individual health and lifestyle factors may modify the relationship between brain-PAD and future cognitive or functional performance. We aimed to identify health-related subgroups of older individuals with resilient or advanced brain-PAD, and determine if membership in these subgroups is differentially associated with changes in cognition and frailty over three to five years. Brain-PAD was predicted from T1-weighted images acquired from 326 community-dwelling older adults (73.8 ± 3.6 years, 42.3% female), recruited from the larger ASPREE (ASPirin in Reducing Events in the Elderly) trial. Participants were grouped as having resilient (n=159) or advanced (n=167) brain-PAD, and latent class analysis (LCA) was performed using a set of cognitive, lifestyle, and health measures. We examined associations of class membership with longitudinal change in cognitive function and frailty deficit accumulation index (FI) using linear mixed models adjusted for age, sex and education. Subgroups of resilient and advanced brain aging were comparable in all characteristics before LCA. Two typically similar latent classes were identified for both subgroups of brain agers: class 1 were characterized by low prevalence of obesity and better physical health and class 2 by poor cardiometabolic, physical and cognitive health. Among resilient brain agers, class 1 was associated with a decrease in cognition, and class 2 with an increase over 5 years, though was a small effect that was equivalent to a 0.04 standard deviation difference per year. No significant class distinctions were evident with FI. For advanced brain agers, there was no evidence of an association between class membership and changes in cognition or FI. These results demonstrate that the relationship between brain age and cognitive trajectories may be influenced by other health-related factors. In particular, people with age-resilient brains had different trajectories of cognitive change depending on their cognitive and physical health status at baseline. Future predictive models of aging outcomes will likely be aided by considering the mediating or synergistic influence of multiple lifestyle and health indices alongside brain age.