White matter lipid alterations during aging in the rhesus monkey brain.

The brain of higher organisms, such as nonhuman primates, is particularly rich in lipids, with a gray to white matter ratio of approximately 40 to 60%. White matter primarily consists of lipids, and during normal aging, it undergoes significant degeneration due to myelin pathology, which includes structural abnormalities, like sheath splitting, and local inflammation. Cognitive decline in normal aging, without neurodegenerative diseases, is strongly linked to myelin pathology. Although the exact cause of myelin damage is unclear, older myelin differs from younger myelin, as shown by electron microscopy and altered expression of myelin-related RNAs. However, changes in lipid composition during brain aging remain poorly understood. This study assessed lipid profiles from the frontal lobe corpus callosum, an area where age-related myelin pathology is linked to cognitive decline. Results showed significant changes in lipids with age, revealing distinct age-related profiles. Some lipids that are enriched in myelin sheaths become more saturated, while important structural components, like ceramides, decrease. Disease-associated biomarkers such as cholesterol ester Che (22:6) and sulfatide ST (42:2) also change in older monkeys. Additionally, gene expression of lipid biosynthetic enzymes declines with age, while lipid peroxidation remains stable in the same brain region. This suggests that changes in lipid biosynthesis, rather than oxidative damage, likely account for the differences in lipid composition. Our findings indicate that myelin in the normal aging monkey brain shows diverse lipid changes, which may relate to age-related myelin pathology and could constitute targets for designing nutrient supplements or drugs to rejuvenate the brain's lipidome.

Chrysin mitigates neuronal apoptosis and impaired hippocampal neurogenesis in male rats subjected to D-galactose-induced brain aging.

Oxidative stress-induced neuronal apoptosis is primarily involved in brain aging and impaired hippocampal neurogenesis. Long-term D-galactose administration increases oxidative stress related to brain aging. Chrysin, a subtype of flavonoids, exhibits neuroprotective effects, particularly its antioxidant properties. To elucidate the neuroprotection of chrysin on neuronal apoptosis and an impaired hippocampal neurogenesis relevant to oxidative damage in D-galactose-induced brain aging, male Sprague Dawley rats were allocated into vehicle control, D-galactose, chrysin, and cotreated rats. The rats received their respective treatments daily for 8 weeks. The reactions of scavenging enzymes, protein regulating endogenous antioxidant defense, and anti-apoptotic protein expression were significantly reduced in the hippocampus and prefrontal cortex of the animals receiving D-galactose. Conversely, product of oxidative damage and apoptotic protein expressions were significantly elevated in both cortical areas of the D-galactose group. In hippocampal neurogenesis, significant upregulation of cell cycle arrest and decrease in differentiated protein expression were detected after D-galactose administration. Nevertheless, chrysin supplementation significantly mitigated all negative effects in animals receiving D-galactose. This study demonstrates that chrysin likely attenuates brain aging induced by D-galactose by enhancing scavenging enzyme activities and reducing oxidative stress, neuronal apoptosis, and the impaired hippocampal neurogenesis.

The ellagitannin metabolite urolithin C attenuated cognitive impairment by inhibiting neuroinflammation via downregulation of MAPK/NF-kB signaling pathways in aging mice.

The current study aimed to evaluate the preventive effects of urolithin C (Uro C), a gut microbial metabolite of ellagitannins on D-galactose (D-gal)-induced brain damage during the aging process and to elucidate the underlying mechanisms. In our study, the protective effect of Uro C on D-gal-induced BV2 microglia cell-mediated neuroinflammation damage in primary cortical neurons in vitro was confirmed. The results in an aging model in vivo induced by D-gal demonstrated that Uro C prevented D-gal-induced memory impairment, long-term potentiation (LTP) damage, and synaptic dysfunction through behavioral, electrophysiological, and histological examinations. Additionally, amyloidogenesis was observed in the central nervous system. The findings indicated that Uro C exhibited a preventive effect on the D-gal-induced elevation of ß-amyloid (1-42 specific) (Aß1-42) accumulation, APP levels, ABCE1 levels, and the equilibrium of the cholinergic system in the aging mouse brain. Moreover, Uro C demonstrated downregulation of D-gal-induced glial overactivation through inhibition of the MAPK/NF-kB pathway. This resulted in the regulation of inflammatory mediators and cytokines, including iNOS, IL-6, IL-1ß, and TNF-ɑ, in the mouse brain and BV2 microglial cells. Taken together, our results suggested that Uro C treatment could effectively mitigate the D-gal-induced memory impairment and amyloidogenesis, and the underlying mechanism might be tightly related to the improvement of neuroinflammation by suppressing the MAPK/NF-kB pathway, indicating Uro C might be an alternative and promising agent for the treatment of aging and age-associated brain diseases.

Cognitive decline and political leadership.

The cognitive deterioration of politicians is a critical emerging issue. As professions including law and medicine develop and implement cognitive assessments, their insights may inform the proper strategy within politics. The aging, lifetime-appointed judiciary raises legal and administrative questions of such assessments, while testing of older physicians experiencing cognitive decline provides real-life examples of implementation. In politics, cognitive assessment must contend with the field's unique challenges, also taking context-dependent interpretations of cognitive-neuropsychological status into account. These perspectives, from legal and medical experts, political scientists, and officeholders, can contribute toward an equitable, functioning, and non-discriminatory system of assessing cognition that educates the public and enables politicians to maintain their public responsibilities. With proper implementation and sufficient public knowledge, we believe cognitive assessments for politicians, particularly political candidates, can be valuable for maintaining properly functioning governance. We offer recommendations on the development, implementation, and execution of such assessments, grappling with their democratic and legal implications.

Unweaving type I interferons in age-related neuroinflammation.

Neuroinflammation is a feature of both neurodegenerative disease and normal brain aging. The roles of type I interferon (IFN-I) in the aged brain are incompletely understood. A recent article by Roy et al. reveals pervasive IFN-I activity in normal mouse brain aging, and highlights the importance of microglial IFN-I signaling in neuroinflammation.

Common and unique brain aging patterns between females and males quantified by large-scale deep learning.

There has been extensive evidence that aging affects human brain function. However, there is no complete picture of what brain functional changes are mostly related to normal aging and how aging affects brain function similarly and differently between males and females. Based on resting-state brain functional connectivity (FC) of 25,582 healthy participants (13,373 females) aged 49-76 years from the UK Biobank project, we employ deep learning with explainable AI to discover primary FCs related to progressive aging and reveal similarity and difference between females and males in brain aging. Using a nested cross-validation scheme, we conduct 4200 deep learning models to classify all paired age groups on the main data for females and males separately and then extract gender-common and gender-specific aging-related FCs. Next, we validate those FCs using additional 21,000 classifiers on the independent data. Our results support that aging results in reduced brain functional interactions for both females and males, primarily relating to the positive connectivity within the same functional domain and the negative connectivity between different functional domains. Regions linked to cognitive control show the most significant age-related changes in both genders. Unique aging effects in males and females mainly involve the interaction between cognitive control and the default mode, vision, auditory, and frontoparietal domains. Results also indicate females exhibit faster brain functional changes than males. Overall, our study provides new evidence about common and unique patterns of brain aging in females and males.

Frequent Alzheimer's disease neuropathological change in patients with glioblastoma.

Background: The incidence of brain cancer and neurodegenerative diseases is increasing with a demographic shift towards aging populations. Biological parallels have been observed between glioblastoma and Alzheimer's disease (AD), which converge on accelerated brain aging. Here, we aimed to map the cooccurrence of AD neuropathological change (ADNC) in the tumor-adjacent cortex of patients with glioblastoma. Methods: Immunohistochemical screening of AD markers amyloid beta (Abeta), amyloid precursor protein (APP), and hyperphosphorylated tau (pTau) was conducted in 420 tumor samples of 205 patients. For each cortex area, we quantified ADNC, neurons, tumor cells, and microglia. Results: Fifty-two percent of patients (N = 106/205) showed ADNC (Abeta and pTau, Abeta or pTau) in the tumor-adjacent cortex, with histological patterns widely consistent with AD. ADNC was positively correlated with patient age and varied spatially according to Thal phases and Braak stages. It decreased with increasing tumor cell infiltration (P < .0001) and was independent of frequent expression of APP in neuronal cell bodies (N = 182/205) and in tumor necrosis-related axonal spheroids (N = 195/205; P = .46). Microglia response was most present in tumor cell infiltration plus ADNC, being further modulated by patient age and sex. ADNC did not impact patient survival in the present cohort. Conclusions: Our findings highlight the frequent presence of ADNC in the glioblastoma vicinity, which was linked to patient age and tumor location. The cooccurrence of AD and glioblastoma seemed stochastic without clear spatial relation. ADNC did not impact patient survival in our cohort.

Brain age prediction via cross-stratified ensemble learning.

As an important biomarker of neural aging, the brain age reflects the integrity and health of the human brain. Accurate prediction of brain age could help to understand the underlying mechanism of neural aging. In this study, a cross-stratified ensemble learning algorithm with staking strategy was proposed to obtain brain age and the derived predicted age difference (PAD) using T1-weighted magnetic resonance imaging (MRI) data. The approach was characterized as by implementing two modules: one was three base learners of 3D-DenseNet, 3D-ResNeXt, 3D-Inception-v4; another was 14 secondary learners of liner regressions. To evaluate performance, our method was compared with single base learners, regular ensemble learning algorithms, and state-of-the-art (SOTA) methods. The results demonstrated that our proposed model outperformed others models, with three metrics of mean absolute error (MAE), root mean-squared error (RMSE), and coefficient of determination (R2) of 2.9405 years, 3.9458 years, and 0.9597, respectively. Furthermore, there existed significant differences in PAD among the three groups of normal control (NC), mild cognitive impairment (MCI) and Alzheimer's disease (AD), with an increased trend across NC, MCI, and AD. It was concluded that the proposed algorithm could be effectively used in computing brain aging and PAD, and offering potential for early diagnosis and assessment of normal brain aging and AD.

ß-Hydroxybutyrate alleviates brain aging through the MTA1 pathway in D-galactose injured mice.

Aging is an inevitable law of the process of life during which many physiological functions change. Brain aging is an important mechanism in the occurrence and development of degenerative diseases of the central nervous system. ß-Hydroxybutyrate (BHBA) is a water-soluble, endogenous small-molecule ketone that can cross the blood-brain barrier and induce neuroprotective effects. This study aimed to investigate the effects of BHBA on D-galactose (D-gal) induced aging in mice and its underlying mechanisms using in vitro and in vivo experiments. These results indicated that D-gal-induced senescence, oxidative stress, and inflammatory responses were inhibited by BHBA, and autophagy was promoted by BHBA. Mechanistically, we explored the role of metastasis-associated antigen-1 (MTA1) in D-gal-induced damaged in HT22 cells using small interfering RNA (siRNA). The results demonstrated that the expression of MTA1 was significantly increased by BHBA, which attenuated D-gal-induced aging, oxidative stress, and inflammatory responses, and promoted autophagy through the upregulation of MTA1. In conclusion, MTA1 may be a novel target for treating aging caused by neurological damage. BHBA improves brain aging by activating the MTA1 pathway.

Alteration of cGAS-STING signaling pathway components in the mouse cortex and hippocampus during healthy brain aging.

The cGAS-STING pathway is a pivotal element of the innate immune system, recognizing cytosolic DNA to initiate the production of type I interferons and pro-inflammatory cytokines. This study investigates the alterations of the cGAS-STING signaling components in the cortex and hippocampus of mice aged 24 and 108 weeks. In the cortex of old mice, an increase in the dsDNA sensor protein cGAS and its product 2'3'-cGAMP was observed, without corresponding activation of downstream signaling, suggesting an uncoupling of cGAS activity from STING activation. This phenomenon may be attributed to increased dsDNA concentrations in the EC neurons, potentially arising from nuclear DNA damage. Contrastingly, the hippocampus did not exhibit increased cGAS activity with aging, but there was a notable elevation in STING levels, particularly in microglia, neurons and astrocytes. This increase in STING did not correlate with enhanced IRF3 activation, indicating that brain inflammation induced by the cGAS-STING pathway may manifest extremely late in the aging process. Furthermore, we highlight the role of autophagy and its interplay with the cGAS-STING pathway, with evidence of autophagy dysfunction in aged hippocampal neurons leading to STING accumulation. These findings underscore the complexity of the cGAS-STING pathway's involvement in brain aging, with regional variations in activity and potential implications for neurodegenerative diseases.

Alzheimer's Disease Neuropathological Change in Aged Non-Primate Mammals.

Human brain aging is characterized by the production and deposition of ß-amyloid (Aß) in the form of senile plaques and cerebral amyloid angiopathy and the intracellular accumulation of hyper-phosphorylated tau (Hp-tau) to form neurofibrillary tangles (NFTs) and dystrophic neurites of senile plaques. The process progresses for years and eventually manifests as cognitive impairment and dementia in a subgroup of aged individuals. Aß is produced and deposited first in the neocortex in most aged mammals, including humans; it is usually not accompanied by altered behavior and cognitive impairment. Hp-tau is less frequent than Aß pathology, and NFTs are rare in most mammals. In contrast, NFTs are familiar from middle age onward in humans; NFTs first appear in the paleocortex and selected brain stem nuclei. NFTs precede for decades or years Aß deposition and correlate with dementia in about 5% of individuals at the age of 65 and 25% at the age of 85. Based on these comparative data, (a) Aß deposition is the most common Alzheimer's disease neuropathological change (ADNC) in the brain of aged mammals; (b) Hp-tau is less common, and NFTs are rare in most aged mammals; however, NFTs are the principal cytoskeletal pathology in aged humans; (c) NFT in aged humans starts in selected nuclei of the brain stem and paleocortical brain regions progressing to the most parts of the neocortex and other regions of the telencephalon; (d) human brain aging is unique among mammalian species due to the early appearance and dramatic progression of NFTs from middle age onward, matching with cognitive impairment and dementia in advanced cases; (e) neither mammalian nor human brain aging supports the concept of the amyloid cascade hypothesis.

Associations between accelerometer-derived sedentary behavior and physical activity with white matter hyperintensities in middle-aged to older adults.

INTRODUCTION: We examined the relationship between sedentary behavior (SB), moderate-to-vigorous physical activity (MVPA), and white matter hyperintensity (WMH) volumes, a common magnetic resonance imaging (MRI) marker associated with risk of neurodegenerative disease in middle-aged to older adults. METHODS: We used data from the UK Biobank (n = 14,415; 45 to 81 years) that included accelerometer-derived measures of SB and MVPA, and WMH volumes from MRI. RESULTS: Both MVPA and SB were associated with WMH volumes (ßMVPA = -0.03 [-0.04, -0.01], p < 0.001; ßSB = 0.02 [0.01, 0.03], p = 0.007). There was a significant interaction between SB and MVPA on WMH volumes (ßSB×MVPA = -0.015 [-0.028, -0.001], p SB×MVPA = 0.03) where SB was positively associated with WMHs at low MVPA, and MVPA was negatively associated with WMHs at high SB. DISCUSSION: While this study cannot establish causality, the results highlight the potential importance of considering both MVPA and SB in strategies aimed at reducing the accumulation of WMH volumes in middle-aged to older adults. Highlights: SB is associated with greater WMH volumes and MVPA is associated with lower WMH volumes.Relationships between SB and WMH are strongest at low levels of MVPA.Associations between MVPA and WMH are strongest at high levels of SB.Considering both SB and MVPA may be effective strategies for reducing WMHs.

Lung function in relation to brain aging and cognitive transitions in older adults: A population-based cohort study.

BACKGROUND: We investigated the association of peak expiratory flow (PEF) with dementia; cognitive impairment, no dementia (CIND); and transition from CIND to dementia, and possible underlying neuropathological mechanisms. METHODS: A population-based cohort of adults aged 60+ was followed over 15 years to detect dementia (Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria), CIND (assessed through a cognitive battery), and progression from CIND to dementia, in relation to baseline PEF observations. A subsample (n = 462) had 6-year follow-up data on brain magnetic resonance imaging markers of neurodegeneration and small vessel disease. RESULTS: In fully adjusted models, poor PEF performance (< 10th vs. ≥ 80th percentile) was associated with increased hazards for dementia (hazard ratio [HR] = 1.89; 95% confidence interval [CI] = 1.23-2.92) and CIND (HR = 1.55; 95% CI = 1.01-2.38) and CIND progression to dementia, although not statistically significantly (HR = 2.44; 95% CI = 0.78-6.88). People with poor PEF also experienced the fastest ventricular enlargement (ß coefficient = 0.67 mL/year; 95% CI = 0.13-1.21) and had the highest likelihood of developing lacunes (odds ratio = 5.05; 95% CI = 1.01-25.23). DISCUSSION: Poor lung function contributes to cognitive deterioration possibly through accelerated brain atrophy and microvascular damage. HIGHLIGHTS: Poor lung function increased the risk of dementia and mild cognitive impairment (MCI). Poor lung function accelerated the progression from MCI to dementia. Poor lung function was linked to brain microvascular damage and global brain atrophy.

Amyloid-ß Pathology Is the Common Nominator Proteinopathy of the Primate Brain Aging.

Senile plaques, mainly diffuse, and cerebral amyloid-ß (Aß) angiopathy are prevalent in the aging brain of non-human primates, from lemurs to non-human Hominidae. Aß but not hyper-phosphorylated tau (HPtau) pathology is the common nominator proteinopathy of non-human primate brain aging. The abundance of Aß in the aging primate brain is well tolerated, and the impact on cognitive functions is usually limited to particular tasks. In contrast, human brain aging is characterized by the early appearance of HPtau pathology, mainly forming neurofibrillary tangles, dystrophic neurites of neuritic plaques, and neuropil threads, preceding Aß deposits by several decades and by its severity progressing from selected nuclei of the brain stem, entorhinal cortex, and hippocampus to the limbic system, neocortex, and other brain regions. Neurofibrillary tangles correlate with cognitive impairment and dementia in advanced cases. Aß pathology is linked in humans to altered membrane protein and lipid composition, particularly involving lipid rafts. Although similar membrane alterations are unknown in non-human primates, membrane senescence is postulated to cause the activated ß-amyloidogenic pathway, and Aß pathology is the prevailing signature of non-human and human primate brain aging.

Pivotal role of AGE-RAGE axis in brain aging with current interventions.

Brain aging is characterized by several structural, biochemical and molecular changes which can vary among different individuals and can be influenced by genetic, environmental and lifestyle factors. Accumulation of protein aggregates, altered neurotransmitter composition, low-grade chronic inflammation and prolonged oxidative stress have been shown to contribute to brain tissue damage. Among key metabolic byproducts, advanced glycation end products (AGEs), formed endogenously through non-enzymatic reactions or acquired directly from the diet or other exogenous sources, have been detected to accumulate in brain tissue, exerting detrimental effects on cellular structure and function, contributing to neurodegeneration and cognitive decline. Upon binding to signal transduction receptor RAGE, AGEs can initiate pro-inflammatory pathways, exacerbate oxidative stress and neuroinflammation, thus impairing neuronal function and cognition. AGE-RAGE signaling induces programmed cell death, disrupts the blood-brain barrier and promotes protein aggregation, further compromising brain health. In this review, we investigate the intricate relationship between the AGE-RAGE pathway and brain aging in order to detect affected molecules and potential targets for intervention. Reduction of AGE deposition in brain tissue either through novel pharmacological therapeutics, dietary modifications, and lifestyle changes, shows a great promise in mitigating cognitive decline associated with brain aging.

Sex-dependent nonlinear Granger connectivity patterns of brain aging in healthy population.

BACKGROUND: Brain aging is a complex process that involves functional alterations in multiple subnetworks and brain regions. However, most previous studies investigating aging-related functional connectivity (FC) changes using resting-state functional magnetic resonance images (rs-fMRIs) have primarily focused on the linear correlation between brain subnetworks, ignoring the nonlinear casual properties of fMRI signals. METHODS: We introduced the neural Granger causality technique to investigate the sex-dependent nonlinear Granger connectivity (NGC) during aging on a publicly available dataset of 227 healthy participants acquired cross-sectionally in Leipzig, Germany. RESULTS: Our findings indicate that brain aging may cause widespread declines in NGC at both regional and subnetwork scales. These findings exhibit high reproducibility across different network sparsities, demonstrating the efficacy of static and dynamic analysis strategies. Females exhibit greater heterogeneity and reduced stability in NGC compared to males during aging, especially the NGC between the visual network and other subnetworks. Besides, NGC strengths can well reflect the individual cognitive function, which may therefore work as a sensitive metric in cognition-related experiments for individual-scale or group-scale mechanism understanding. CONCLUSION: These findings indicate that NGC analysis is a potent tool for identifying sex-dependent brain aging patterns. Our results offer valuable perspectives that could substantially enhance the understanding of sex differences in neurological diseases in the future, especially in degenerative disorders.

Examining the influence of self-care practices on brain activity in healthy older adults.

Introduction: Studies on the aging brain often occur in active settings, but comparatively few investigate brain activity in resting states. However, exploring brain activity in a resting state offers valuable insights into spontaneous neural processes unaffected by task-specific influences. Objective: To investigate the relationship between self-care practices, cognitive function, and patterns of brain activity in healthy older adults, taking into account predictions from aging brain models. Methodology: 77 older adults aged 61 to 87 completing a self-care practices questionnaire, neuropsychological tests, and resting-state electroencephalogram (EEG) recordings. Participants were classified into two groups according to their self-care practices: traditional self-care (T-SC) and developmental self-care (D-SC). Results: Although neuropsychological tests did not yield significant differences between the D-SC and T-SC groups, patterns of brain activity revealed distinct behaviors. The T-SC group demonstrated patterns more consistent with established aging brain models, contrasting with the D-SC group, which exhibited brain activity akin to that observed in younger adults. Specifically, the T-SC group displayed hyperactivation related to memory and executive function performance, alongside heightened alpha power in posterior regions. Furthermore, bilateral frontal activation in the beta band was evident. Conclusions: The findings suggest a nuanced relationship between self-care practices and brain activity in older adults. While the T-SC group demonstrated brain activity patterns consistent with conservative aging, indicating the preservation of typical aging characteristics, the D-SC group displayed activity suggestive of a potential protective effect. This effect may be linked to self-care strategies that foster development and resilience in cognitive aging.

Understanding the Temporal Dynamics of Accelerated Brain Aging and Resilient Brain Aging: Insights from Discriminative Event-Based Analysis of UK Biobank Data.

The intricate dynamics of brain aging, especially the neurodegenerative mechanisms driving accelerated (ABA) and resilient brain aging (RBA), are pivotal in neuroscience. Understanding the temporal dynamics of these phenotypes is crucial for identifying vulnerabilities to cognitive decline and neurodegenerative diseases. Currently, there is a lack of comprehensive understanding of the temporal dynamics and neuroimaging biomarkers linked to ABA and RBA. This study addressed this gap by utilizing a large-scale UK Biobank (UKB) cohort, with the aim to elucidate brain aging heterogeneity and establish the foundation for targeted interventions. Employing Lasso regression on multimodal neuroimaging data, structural MRI (sMRI), diffusion MRI (dMRI), and resting-state functional MRI (rsfMRI), we predicted the brain age and classified individuals into ABA and RBA cohorts. Our findings identified 1949 subjects (6.2%) as representative of the ABA subpopulation and 3203 subjects (10.1%) as representative of the RBA subpopulation. Additionally, the Discriminative Event-Based Model (DEBM) was applied to estimate the sequence of biomarker changes across aging trajectories. Our analysis unveiled distinct central ordering patterns between the ABA and RBA cohorts, with profound implications for understanding cognitive decline and vulnerability to neurodegenerative disorders. Specifically, the ABA cohort exhibited early degeneration in four functional networks and two cognitive domains, with cortical thinning initially observed in the right hemisphere, followed by the temporal lobe. In contrast, the RBA cohort demonstrated initial degeneration in the three functional networks, with cortical thinning predominantly in the left hemisphere and white matter microstructural degeneration occurring at more advanced stages. The detailed aging progression timeline constructed through our DEBM analysis positioned subjects according to their estimated stage of aging, offering a nuanced view of the aging brain's alterations. This study holds promise for the development of targeted interventions aimed at mitigating age-related cognitive decline.

Harnessing myelin water fraction as an imaging biomarker of human cerebral aging, neurodegenerative diseases, and risk factors influencing myelination: A review.

Myelin water fraction (MWF) imaging has emerged as a promising magnetic resonance imaging (MRI) biomarker for investigating brain function and composition. This comprehensive review synthesizes the current state of knowledge on MWF as a biomarker of human cerebral aging, neurodegenerative diseases, and risk factors influencing myelination. The databases used include Web of Science, Scopus, Science Direct, and PubMed. We begin with a brief discussion of the theoretical foundations of MWF imaging, including its basis in MR physics and the mathematical modeling underlying its calculation, with an overview of the most adopted MRI methods of MWF imaging. Next, we delve into the clinical and research applications that have been explored to date, highlighting its advantages and limitations. Finally, we explore the potential of MWF to serve as a predictive biomarker for neurological disorders and identify future research directions for optimizing MWF imaging protocols and interpreting MWF in various contexts. By harnessing the power of MWF imaging, we may gain new insights into brain health and disease across the human lifespan, ultimately informing novel diagnostic and therapeutic strategies.

NODDI in gray matter is a sensitive marker of aging and early AD changes.

INTRODUCTION: Age-related and Alzheimer's disease (AD) dementia-related neurodegeneration impact brain health. While morphometric measures from T1-weighted scans are established biomarkers, they may be less sensitive to earlier changes. Neurite orientation dispersion and density imaging (NODDI), offering biologically meaningful interpretation of tissue microstructure, may be an advanced brain health biomarker. METHODS: We contrasted regional gray matter NODDI and morphometric evaluations concerning their correlation with (1) age, (2) clinical diagnosis stage, and (3) tau pathology as assessed by AV1451 positron emission tomography. RESULTS: Our study hypothesizes that NODDI measures are more sensitive to aging and early AD changes than morphometric measures. One NODDI output, free water fraction (FWF), showed higher sensitivity to age-related changes, generally better effect sizes in separating mild cognitively impaired from cognitively unimpaired participants, and stronger associations with regional tau deposition than morphometric measures. DISCUSSION: These findings underscore NODDI's utility in capturing early neurodegenerative changes and enhancing our understanding of aging and AD. Highlights: Neurite orientation dispersion and density imaging can serve as an effective brain health biomarker for aging and early Alzheimer's disease (AD).Free water fraction has higher sensitivity to normal brain aging.Free water fraction has stronger associations with early AD and regional tau deposition.