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Microglia, the immune cells in the brain, play a significant role in the pathophysiology of neurodegenerative diseases. To visualize these cells in the living brain, we developed a PET ligand, [ 11 C]NCGG401 (4-{2-[((1 R ,2 R )-2-hydroxycyclohexyl)(methyl)amino]benzothiazol-6-yloxy}- N -methylpicolinamide, NCGG401), that targets colony-stimulating factor 1 receptor (CSF1R). In this study, we present the first-in-human evaluation of [ 11 C]NCGG401 to assess its safety profile and then to evaluate its kinetics to quantify CSF1R in the human brain. Methods: Head to upper thigh PET scans were conducted in 3 healthy men to estimate the effective dose of [ 11 C]NCGG401. Brain PET scans were performed on 6 healthy men, combined with arterial blood sampling and metabolite analyses. Compartmental and graphical models were used to quantify CSF1R in the human brain. [ 11 C]NCGG401 PET data were indirectly compared with regional CSF1R protein levels after death that were reported in a proteomics study. In addition, the results of this study were directly compared with the PET imaging of 18-kDa translocator protein using [ 11 C]DPA-713 ( N , N -diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl]acetamide, DPA-713). Results: The administration of [ 11 C]NCGG401 did not result in severe adverse events. The effective doses per injected activity were 5.1 ± 0.2 µSv/MBq for men and 6.1 ± 0.3 µSv/MBq for women. [ 11 C]NCGG401 demonstrated good brain permeability, with peak uptake reaching an SUV of 3. Regional total distribution volumes were reliably quantified using the 2-tissue compartment model and a Logan plot with 60 min of scan data. The resulting parametric images reflected the known distribution of CSF1R in the brain. Furthermore, regional total distribution volume values of [ 11 C]NCGG401 showed good correlation with regional CSF1R protein levels. The [ 11 C]NCGG401 images showed regional distributions different from those of [ 11 C]DPA-713. Conclusion: [ 11 C]NCGG401 images appear to reflect regional microglia-specific distributions of CSF1R in the brain, consistent with the findings of a CSF1R proteomics study by others. However, ultimate confirmation of specific CSF1R binding should be validated by evaluating, in suitable preclinical or human experiments, pharmacologic blockade of its binding in the brain in vivo., (© 2025 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: POINTER Neurovascular (POINTER-NV) is an ancillary study that leverages the rich infrastructure and design of the U.S. Study to Protect Brain Health through Lifestyle Intervention to Reduce Risk (U.S. POINTER) to investigate neurovascular mechanisms that may underlie intervention effects on key brain outcomes., Methods: A comprehensive neurovascular assessment is conducted at baseline, Month 12, and Month 24 using a variety of complementary non-invasive techniques including transcranial Doppler ultrasound, carotid ultrasound, echocardiography, tonometry, and continuous blood pressure and heart rate monitoring. Measurements are acquired at rest and during orthostatic challenges, hyperventilation, and carbon dioxide inhalation., Results: The primary outcomes are baroreflex sensitivity and cerebral autoregulation. Secondary outcomes include aortic, carotid, and cerebral hemodynamics and various measures of autonomic function and vascular structure and function., Discussion: POINTER-NV will provide critical insight into neurovascular mechanisms that may change with intensive lifestyle modification and promote improvements in cognition and overall brain health., Highlights: This study takes advantage of U.S. Study to Protect Brain Health through Lifestyle Intervention to Reduce Risk (U.S. POINTER) to address key gaps in the field. POINTER Neurovascular (POINTER-NV) will provide insight into neurovascular mechanisms underlying dementia. POINTER-NV may help shed light on modifiable vascular contributions to dementia., (© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Dual cognitive and mobility decline is more strongly associated with dementia risk than cognitive decline only. It remains unknown whether this syndrome is associated with brain atrophy patterns, white matter (WM) damage, or pathology., Methods: In the Baltimore Longitudinal Study of Aging participants with and without dual decline, we used linear mixed-effects models to compare up to 13-year longitudinal changes in MRI-derived atrophy patterns, WM hyperintensities (n = 339), microstructure (n = 307), plasma glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), amyloid beta 42/40 (Aβ 42/40 ) ratio (n = 349), and phosphorylated tau 181 (pTau181) (n = 258)., Results: Those experiencing dual decline showed accelerated atrophy in medial temporal (p = .004), parietotemporal (p = .029), and perisylvian regions (p = .028), whereas gait decline only showed accelerated parietotemporal atrophy (p = .035) and memory decline only showed perisylvian atrophy (p = .021). Dual decline was also associated with unique microstructural deterioration in several WM tracts (p < .05), a greater decrease in Aβ 42/40 ratio (p = .015), and greater increases in GFAP (p = .009) and NfL (p < .001)., Discussion: Individuals experiencing dual decline are at an increased risk for regional brain atrophy, microstructural degradation, and biomarker-defined molecular changes underlying dementia., Highlights: Those experiencing dual decline showed several accelerated brain atrophy patterns. Those experiencing dual decline showed unique microstructural deterioration. Dual decline showed a greater decline in plasma Aβ 42/40 ratio. Dual decline showed greater increases in plasma GFAP and NfL. Dual decline may indicate brain and blood markers underlying dementia., (© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Extracellular vesicles (EVs) have emerged as novel blood-based biomarkers for various pathologies. The development of methods to enrich cell-specific EVs from biofluids has enabled us to monitor difficult-to-access organs, such as the brain, in real time without disrupting their function, thus serving as liquid biopsy. Burgeoning evidence indicates that the contents of neuron-derived EVs (NDEs) in blood reveal dynamic alterations that occur during neurodegenerative pathogenesis, including Alzheimer's disease (AD), reflecting a disease-specific molecular signature. Among these AD-specific molecular changes is brain insulin-signaling dysregulation, which cannot be assessed clinically in a living patient and remains an unexplained co-occurrence during AD pathogenesis. This review is focused on delineating how NDEs in the blood may begin to close the gap between identifying molecular changes associated with brain insulin dysregulation reliably in living patients and its connection to AD. This approach could lead to the identification of novel early and less-invasive diagnostic molecular biomarkers for AD. HIGHLIGHTS: Neuron-derived extracellular vesicles (NDEs) could be isolated from peripheral blood. NDEs in blood reflect the molecular signature of Alzheimer's disease (AD). Brain insulin-signaling dysregulation plays a critical role in AD. NDEs in blood could predict brain insulin-signaling dysregulation. NDEs offer novel early and less-invasive diagnostic biomarkers for AD., (© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Inter-brain synchrony occurs between individuals who feel connected socially, but how synchrony relates to felt connectedness under naturalistic social interaction has remained enigmatic. We hypothesized that inter-brain synchrony between naturally interacting individuals might be associated with the internalization of a social identity, a link between an individual's personal identity and the social group to which the individual belongs. A convenience sample of sixty participants were split into dyads and interacted naturalistically on a social task. Through mapping EEG oscillatory waveforms onto a conceptual model categorizing the formation of a social identity within a naturalistic conversation, greater inter-brain synchrony was observed in the emergent stage within the formation of a social identity compared to earlier stages, where a social identity was not present. We provide evidence for greater neural synchrony related to higher socio-psychological connectedness during the development of social identity under naturalistic social interaction., (© 2024 The Author(s). British Journal of Psychology published by John Wiley & Sons Ltd on behalf of The British Psychological Society.)

Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). We identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein solubility. βHB primarily provides ATP substrate during periods of reduced glucose availability, and regulates other cellular processes through protein interactions. We demonstrate βHB-induced protein insolubility is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain in vivo after delivery of a ketone ester. This mechanism is selective for pathological proteins such as amyloid-β, and exogenous βHB ameliorates pathology in nematode models of amyloid-β aggregation toxicity. We generate libraries of the βHB-induced protein insolublome using mass spectrometry proteomics, and identify common protein domains and upstream regulators. We show enrichment of neurodegeneration-related proteins among βHB targets and the clearance of these targets from mouse brain. These data indicate a metabolically regulated mechanism of proteostasis relevant to aging and AD., Competing Interests: Declaration of interests J.C.N. and E.V. hold patents related to molecules described herein, licensed to BHB Therapeutics Ltd and Selah Therapeutics Ltd. J.C.N. and E.V. are co-founders with stock holdings, and BJS holds stock options, in BHB Therapeutics. J.C.N., E.V., and B.S. are co-founders with stock holdings in Selah Therapeutics., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Every cell in the body has a biological sex. The expansion of aging research to investigate female- and male-specific biology heralds a major advance for human health. Unraveling and harnessing mechanistic etiologies of sex differences may reveal new diagnostics and therapeutics for the aging brain., Competing Interests: Declaration of interests D.B.D. consulted for Unity Biotechnology and SV Health Investors, serves on the board of the Glenn Foundation for Medical Research, and is an associate editor for JAMA Neurology., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The cognitive neuroscience of human aging seeks to identify neural mechanisms behind the commonalities and individual differences in age-related behavioral changes. This goal has been pursued predominantly through structural or "task-free" resting-state functional neuroimaging. The former has elucidated the material foundations of behavioral decline, and the latter has provided key insight into how functional brain networks change with age. Crucially, however, neither is able to capture brain activity representing specific cognitive processes as they occur. In contrast, task-based functional imaging allows a direct probe into how aging affects real-time brain-behavior associations in any cognitive domain, from perception to higher-order cognition. Here, we outline why task-based functional neuroimaging must move center stage to better understand the neural bases of cognitive aging. In turn, we sketch a multi-modal, behavior-first research framework that is built upon cognitive experimentation and emphasizes the importance of theory and longitudinal design., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Considering that a multifactorial lifestyle approach may prove more effective than a single factor approach to improve or maintain brain health, we evaluated the association of exercise (open skill exercise [OSE] or closed skill exercise [CSE]) combined with long-chain polyunsaturated fatty acid (LCPUFAs) (docosahexaenoic acid [C22:6n-3, DHA], eicosapentaenoic acid [C20:5n-3, EPA], and arachidonic acid [C20:4n-6, ARA]) intake with brain atrophy among older Japanese individuals (n = 795, aged 60-88 years) without a self-reported history of dementia based on the datasets of a two-year longitudinal study. Brain volumes were measured using three-dimensional T1-weighted brain magnetic resonance imaging for follow-up periods of two years. The associations between multivariate-adjusted changes in brain volumes and OSE or CSE frequency (≥ once/month and < once/month) along with LCPUFA intake (≥ median and < median) at the baseline were assessed using a general linear model. Subgroup analysis was performed by restricting DHA and EPA intakes (n = 263; median, 323 mg/d), which represented levels similar to those in countries with low fish consumption. Higher OSE frequencies, ARA intakes, and their combination were inversely associated with decreases in total gray matter and frontal cortex volumes. In subgroup analysis, a combination of higher OSE frequencies and DHA intakes was also associated with a smaller decrease in total gray matter volume. Overall, our findings suggest that regular OSE engagement and appropriate LCPUFA intake may contribute to preventing brain volume decreases in older individuals., Competing Interests: Declaration of competing interest HT, CH, YK, TI, and YN are employees of Suntory Wellness Ltd., which markets health food products that include LCPUFAs. The other authors declare no conflicts of interest regarding this study., (Copyright © 2024. Published by Elsevier B.V.)

Background: The association of Mini-Mental State Examination (MMSE) with microstructure of individual regions across the entire brain remains unexplored., Purpose: To investigate the relationship between cognitive function and the microstructure of each brain region in the gray matter using diffusion kurtosis imaging (DKI) in older adults with mild cognitive impairment (MCI), which is the transitional stage before the onset of dementia., Material and Methods: DKI and MMSE were obtained for 34 older adults with MCI and 16 cognitively normal (CN) individuals aged 65-85 years. The DKI parameters were measured from 31 distinct regions of interest in the gray matter. A multiple regression analysis was used to examine the association between DKI parameters and MMSE scores; subsequently, interactions between the DKI parameters and the groups (MCI and CN) were examined., Results: The mean (±SD) MMSE score for the MCI group was 27.67 ± 1.90. Significant positive correlations were observed between MMSE score and mean kurtosis (MK) in the superior frontal, middle frontal, inferior frontal, precentral, postcentral, angular, middle temporal, and inferior occipital gyri, and superior parietal lobe for the MCI group. In addition, the interaction term of the MK in the middle frontal, precentral, postcentral, and angular gyri, and the groups was statistically significant., Conclusion: Older adults with MCI may exhibit histological damage in certain regions of the brain, such as the middle frontal and angular gyri, as observed in this study. The findings could provide insights into understanding the pathophysiology of cognitive decline in this population group., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Magnetization prepared rapid acquisition with gradient echo (MPRAGE) sequence is a gold-standard technique for voxel-based morphometry (VBM) because of high spatial resolution and excellent tissue contrast, especially between gray matter (GM) and white matter (WM). Despite its benefits, MPRAGE exhibits distinct challenge for VBM in some patients with neurological disease because of long scan time and motion artifacts. Speedily acquired localizer images may alleviate this problem. This study aimed to evaluate the feasibility of VBM using 3D Fast Low Angle Shot image captured for localizer (L3DFLASH)., Methods: Consecutive 13 patients with pathologically confirmed Alzheimer's disease (AD) (82 ± 9 years) and 21 healthy controls (HC) (79 ± 4 years) were included in this study. Whole-brain L3DFLASH and MPRAGE were captured and preprocessed using the Computational Anatomy Toolbox 12 (CAT12). Agreement with MPRAGE was evaluated for L3DFLASH using regional normalized volume for segmented brain areas. In addition to brain volume difference on VBM and Bland-Altman analysis, atrophic pattern of AD on VBM was evaluated using L3DFLASH and MPRAGE., Results: Acquisition time was 18 s for L3DFLASH and 288 s for MPRAGE. There was a slight systematic difference in all regional normalized volumes from L3DFLASH and MPRAGE. For the whole cohort, GM volume measured from MPRAGE was greater than that from L3DFLASH in most of the region on VBM. When AD and HC were compared, AD-related atrophic pattern was demonstrated in both L3DFLASH and MPRAGE on VBM, although the difference was noted in significant clusters between them., Conclusion: Although systematic difference was noted in regional brain volume measured from L3DFLASH and MPRAGE, AD-related atrophic pattern was preserved in L3DFLASH on VBM. VBM, using speedily acquired localizer image, may provide limited but useful information for evaluating brain atrophy.

Introduction: The factors that influence the progression of Alzheimer's disease (AD) after individuals become amyloid-positive are poorly understood. This study examines how sex influences the longitudinal trajectories of plasma AD and neurodegenerative biomarkers in the years following a person's estimated onset of amyloid-β., Methods: Linear mixed-effects modeling investigated overall and sex-specific longitudinal trajectories of plasma biomarkers, brain volumes, and cognition relative to the estimated age of amyloid onset in a cohort of 78 amyloid-positive Baltimore Longitudinal Study of Aging (BLSA) participants (n = 45 male; follow-up time: 6.8 years [SD 3.31]). Amyloid status was ascertained with 11 C-Pittsburgh compound B (PiB) PET imaging., Results: After amyloid onset, men displayed steeper increases in pTau181, pTau231, and neurofilament light (NfL) compared to women. In this same period, men demonstrated steeper declines in brain volume and cognitive performance., Discussion: These findings suggest that sex influences the trajectory of AD pathology, neuronal injury, and symptom progression after individuals become amyloid-positive., Highlights: Steeper rates of increase in pTau and GFAP among amyloid-positive individuals. After amyloid onset, steeper increases in pTau and NfL concentrations in men than in women. Steeper declines in brain volume and cognition in men corroborate biomarker results., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Introduction: Iron-mediated cell death (ferroptosis) is a proposed mechanism of Alzheimer's disease (AD) pathology. While iron is essential for basic biological functions, its reactivity generates oxidants which contribute to cell damage and death., Methods: To further resolve mechanisms of iron-mediated toxicity in AD, we analyzed post mortem human brain and ApoEFAD mice., Results: AD brains had decreased antioxidant enzymes, including those mediated by glutathione (GSH). Subcellular analyses of AD brains showed greater oxidative damage and lower antioxidant enzymes in lipid rafts, the site of amyloid processing, than in the non-raft membrane fraction. Apolipoprotein E ε4 carriers had lower lipid raft yield with greater membrane oxidation. The hypothesized role of iron in AD pathology was tested in ApoEFAD mice by iron chelation with deferoxamine, which decreased fibrillar amyloid and lipid peroxidation, together with increased GSH-mediated antioxidants., Discussion: These novel molecular pathways highlight iron-mediated damage to lipid rafts during AD., Highlghts: Alzheimer's disease (AD) brains have numerous markers for ferroptosis, including increased lipid peroxidation, reduced antioxidant levels, and increased iron storage. Lipid rafts in AD cases have increased oxidative damage and reduced antioxidant enzyme levels and activity which are most severe in apolipoprotein E ε4 carriers. Neuronal markers are correlated with lipid peroxidation, antioxidant defense, and iron signaling proteins suggesting that neuronal loss is linked to these events. Chelation of iron in the early-onset familial AD model reduces iron-mediated lipid peroxidation and fibrillar amyloid., (© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Childhood adversity harms neurodevelopment. Literature on late-life brain health is limited, and findings on late-life cognition are mixed., Methods: Pooling data from Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) and Study of Healthy Aging in African Americans (STAR) cohorts, we assessed the impact of childhood adversity (factor score from seven self-reported items) on (a) executive function and verbal memory decline using linear mixed effects models (n = 2447), (b) structural magnetic resonance imaging (MRI) using linear regression (n = 618), and (c) amyloid positron emission tomography (PET) using generalized linear models (n = 331), all adjusting for early-life demographic and socioeconomic confounders., Results: Childhood adversity was not associated with cognition except for a slightly faster decline in verbal memory ( β ̂ $\hat \beta $  = -0.013 SD/year, 95% confidence interval [-0.025, -0.001]). Among neuroimaging outcomes, childhood adversity was associated with only larger temporal lobe volumes ( β ̂ $\hat \beta $  = 0.092 SD [0.012, 0.173])., Discussion: More research evaluating sources of resilience, heterogeneity, and bias is needed to explain inconsistent findings across studies., Highlights: We developed measurement models to capture childhood adversity in a diverse cohort. Childhood adversity was associated with a slightly faster verbal memory decline. We examined childhood adversity's effect on structural MRI and amyloid PET measures. Higher childhood adversity was associated with larger temporal lobe volumes., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Impaired muscle mitochondrial oxidative capacity is associated with future cognitive impairment, and higher levels of PET and blood biomarkers of Alzheimer's disease and neurodegeneration. Here, we examine its associations with up to over a decade-long changes in brain atrophy and microstructure. Higher in vivo skeletal muscle oxidative capacity via MR spectroscopy (post-exercise recovery rate, k PCr ) is associated with less ventricular enlargement and brain aging progression, and less atrophy in specific regions, notably primary sensorimotor cortex, temporal white and gray matter, thalamus, occipital areas, cingulate cortex, and cerebellum white matter. Higher k PCr is also associated with less microstructural integrity decline in white matter around cingulate, including superior longitudinal fasciculus, corpus callosum, and cingulum. Higher in vivo muscle oxidative capacity is associated with preserved brain structure up to over a decade, particularly in areas important for cognition, motor function, and sensorimotor integration., Competing Interests: Competing interests: The Authors declare no competing interests., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Neuroinflammatory and neurodegenerative diseases are influenced by the complex interplay of different cell types within the brain, and understanding the proportions and dynamics of neuronal, glial, and endothelial cells is crucial for deciphering the mechanisms of these diseases. Certain risk factors, such as age and sex differences, are thought to play a significant role in the susceptibility, progression, and response to neurological disease. Therefore, investigation of age- and sex-related differences in cell type proportions is needed to elucidate the biological basis of these diseases. Advances in sequencing technology have enabled large-scale transcriptomic studies, such as the Genotype-Tissue Expression (GTEx) project, providing valuable resources for investigating the cellular landscape of the human brain. In this analysis, we used brain sample data from the GTEx project, comprising 1646 samples with an age range of 20-70 years. The relative abundance of excitatory and inhibitory neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells was estimated from the RNA sequencing data using a deconvolution-based analysis. Spearman correlation analysis between the individuals' calendar ages and cell type proportions revealed a statistically significant decrease in the proportion of neurons with increasing age. In contrast, the proportions of astrocytes and endothelial cells showed a significant increase. Furthermore, endothelial cells exhibited the strongest correlation coefficient, positively associating with age. In addition, the findings indicate sex-based differences in age-related changes to cell type proportions. An age-associated decrease in neuronal proportions was only observed in male donors, while no significant change was found in females. Additionally, an age-associated increase in astrocyte proportions was exclusively seen in males, whereas only females exhibited a significant increase in microglia proportions. Furthermore, we identified sex-based differences in baseline cell type proportions. Male originating samples exhibited higher proportions of excitatory neurons, while female samples showed higher proportions of microglia and endothelial cells. Our results show that both age and sex affect the proportions of cell types in non-diseased brain tissue samples. These findings contribute to our understanding of the effects of age and sex differences on the cellular composition of the brain and shed light on the potential roles of age and sex in neurological diseases., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Autio-Kimura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Iron is necessary for many neurobiological mechanisms, but its overaccumulation can be harmful. Factors triggering age-related brain iron accumulation remain largely unknown and longitudinal data are insufficient. We examined associations between brain iron load and accumulation and, blood markers of iron metabolism, cardiovascular health, lifestyle factors (smoking, alcohol use, physical activity, diet), and ApoE status using longitudinal data from the IronAge study (n = 208, age = 20-79, mean follow-up time = 2.75 years). Iron in cortex and basal ganglia was estimated with magnetic resonance imaging using quantitative susceptibility mapping (QSM). Our results showed that (1) higher peripheral iron levels (i.e., composite score of blood iron markers) were related to greater iron load in the basal ganglia; (2) healthier diet was related to higher iron levels in the cortex and basal ganglia, although for the latter the association was significant only in younger adults (age = 20-39); (3) worsening cardiovascular health was related to increased iron accumulation; (4) younger ApoE ε4 carriers accumulated more iron in basal ganglia than younger non-carriers. Our results demonstrate that modifiable factors, including lifestyle, cardiovascular, and physiological ones, are linked to age-related brain iron content and accumulation, contributing novel information on potential targets for interventions in preventing brain iron-overload., Competing Interests: Declaration of Competing Interest None, (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Slice-to-volume registration and super-resolution reconstruction are commonly used to generate 3D volumes of the fetal brain from 2D stacks of slices acquired in multiple orientations. A critical initial step in this pipeline is to select one stack with the minimum motion among all input stacks as a reference for registration. An accurate and unbiased motion assessment (MA) is thus crucial for successful selection. Here, we presented an MA method that determines the minimum motion stack based on 3D low-rank approximation using CANDECOMP/PARAFAC (CP) decomposition. Compared to the current 2D singular value decomposition (SVD) based method that requires flattening stacks into matrices to obtain ranks, in which the spatial information is lost, the CP-based method can factorize 3D stack into low-rank and sparse components in a computationally efficient manner. The difference between the original stack and its low-rank approximation was proposed as the motion indicator. Experiments on linearly and randomly simulated motion illustrated that CP demonstrated higher sensitivity in detecting small motion with a lower baseline bias, and achieved a higher assessment accuracy of 95.45% in identifying the minimum motion stack, compared to the SVD-based method with 58.18%. CP also showed superior motion assessment capabilities in real-data evaluations. Additionally, combining CP with the existing SRR-SVR pipeline significantly improved 3D volume reconstruction. The results indicated that our proposed CP showed superior performance compared to SVD-based methods with higher sensitivity to motion, assessment accuracy, and lower baseline bias, and can be used as a prior step to improve fetal brain reconstruction., (© 2024 John Wiley & Sons, Ltd.)

Large-scale brain networks undergo functional reorganization over the course of the lifespan, with concurrent implications for cognition. Characterizing network connectivity during a task may provide complementary insight into cognitive development and aging, to that provided by resting-state. We assessed network background connectivity, which refers to connectivity that remains after task effects have been regressed out, during a visual memory-encoding task in a lifespan sample. More specifically we assessed the within- and between-network background connectivity of the default mode, salience, and frontoparietal networks. Within-network background connectivity of salience and frontoparietal networks differed between age groups, with late-life adults showing lower connectivity. We did not find an effect of age group in default mode network background connectivity, contrary to previous findings using resting-state. However, default mode between-network background connectivity with salience and frontoparietal networks was greater in mid-life and late-life adults than in younger age groups. Overall, our findings in a lifespan sample are in line with previous observations of age-related network de-differentiation. However, the lack of age effect in default mode network background connectivity suggests that background connectivity indeed represents a complementary measure to resting-state connectivity, providing a differential glance of network connectivity during a particular state., Competing Interests: Declarations of interest None., (Copyright © 2022 Japan Neuroscience Society and Elsevier B.V. All rights reserved.)

Brain age (BA), distinct from chronological age (CA), can be estimated from MRIs to evaluate neuroanatomic aging in cognitively normal (CN) individuals. BA, however, is a cross-sectional measure that summarizes cumulative neuroanatomic aging since birth. Thus, it conveys poorly recent or contemporaneous aging trends, which can be better quantified by the (temporal) pace P of brain aging. Many approaches to map P , however, rely on quantifying DNA methylation in whole-blood cells, which the blood-brain barrier separates from neural brain cells. We introduce a three-dimensional convolutional neural network (3D-CNN) to estimate P noninvasively from longitudinal MRI. Our longitudinal model (LM) is trained on MRIs from 2,055 CN adults, validated in 1,304 CN adults, and further applied to an independent cohort of 104 CN adults and 140 patients with Alzheimer's disease (AD). In its test set, the LM computes P with a mean absolute error (MAE) of 0.16 y (7% mean error). This significantly outperforms the most accurate cross-sectional model, whose MAE of 1.85 y has 83% error. By synergizing the LM with an interpretable CNN saliency approach, we map anatomic variations in regional brain aging rates that differ according to sex, decade of life, and neurocognitive status. LM estimates of P are significantly associated with changes in cognitive functioning across domains. This underscores the LM's ability to estimate P in a way that captures the relationship between neuroanatomic and neurocognitive aging. This research complements existing strategies for AD risk assessment that estimate individuals' rates of adverse cognitive change with age., Competing Interests: Competing interests statement:The authors declare no competing interest.

Although the concept that the blood-brain barrier (BBB) plays an important role in the etiology and pathogenesis of Alzheimer's disease (AD) has become increasingly accepted, little is known yet about how it actually contributes. We and others have recently identified a novel functionally distinct subset of BBB pericytes (PCs). In the present study, we sought to determine whether these PC subsets differentially contribute to AD-associated pathologies by immunohistochemistry and amyloid beta (Aβ) peptidomics. We demonstrated that a disease-associated PC subset (PC2) expanded in AD patients compared to age-matched, cognitively unimpaired controls. Surprisingly, we found that this increase in the percentage of PC2 (%PC2) was correlated negatively with BBB breakdown in AD patients, unlike in natural aging or other reported disease conditions. The higher %PC2 in AD patients was also correlated with a lower Aβ42 plaque load and a lower Aβ42:Aβ40 ratio in the brain as determined by immunohistochemistry. Colocalization analysis of multicolor confocal immunofluorescence microscopy images suggests that AD patient with low %PC2 have higher BBB breakdown due to internalization of Aβ42 by the physiologically normal PC subset (PC1) and their concomitant cell death leading to more vessels without PCs and increased plaque load. On the contrary, it appears that PC2 can secrete cathepsin D to cleave and degrade Aβ built up outside of PC2 into more soluble forms, ultimately contributing to less BBB breakdown and reducing Aβ plaque load. Collectively our data shows functionally distinct mechanisms for PC1 and PC2 in high Aβ conditions, demonstrating the importance of correctly identifying these populations when investigating the contribution of neurovascular dysfunction to AD pathogenesis., (© 2024 The Author(s). Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Triazolium α-cyclodextrin click cluster-magnetic agarose bead conjugate ( + CCC-MAB) was used to enrich phosphatidylinositol bisphosphates in brain tissue. The enriched sample was phosphate-methylated and analyzed by MALDI-TOF-MS/MS in positive ion mode. + CCC-MAB effectively removed weak-binding interferences from the phosphoinositide extract and improved the signal-to-noise ratio. The MALDI-TOF-MS/MS fragment ion revealed sodium adducts of polar head groups, exhibiting a converse fragmentation pattern compared to LC-ESI fragmentation. Our  + CCC-MAB-based phosphoinositide enrichment method enabled MALDI-TOF-MS/MS to assign 38 peaks in brain tissue and identify two phosphatidylinositol monophosphates, fifteen bisphosphates, and two trisphosphates. To our knowledge, this is the first study to analyze phosphatidylinositol bisphosphates in brain tissue using specific PIP enrichment and phosphate-methylation with MALDI-TOF-MS/MS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Slow gait speed and disrupted brain network connectivity are common in patients with Parkinson's disease (PD). This study aimed to clarify the relationship between gait speed and clinical characteristics in PD, and explore the underlying brain network mechanisms. Forty-two PD patients and 20 healthy controls (HC) were recruited. Statistical independent component analysis and correlation analysis were employed to investigate underlying neural mechanisms and relationships. PD patients exhibited significantly slower gait speed, which showed a significant negative correlation with postural instability and gait disturbance scores. Network connectivity analysis revealed decreased intranetwork functional connectivity (FC) within visual network (VN) and cerebellum network (CN), but increased internetwork FC between CN and both sensorimotor network (SMN) and frontoparietal network (FPN) in PD patients compared to HC. The slow gait speed PD subgroup demonstrated increased intranetwork FC within SMN and VN, along with decreased FC between VN and both FPN and default mode network. Correlation analyses revealed negative correlation between gait speed and FC of CN and positive correlation to FC of CN-SMN. Our study identified relationships between gait speed and clinical characteristics, and corresponding network connectivity alterations in PD patients, providing insights into the neural mechanisms underlying gait impairments in PD., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background Synaptic loss is an important factor in Alzheimer disease (AD); however, blood assays that conveniently and rapidly reflect changes in synaptic density are lacking. Purpose To correlate multiple potential synaptic blood markers with synaptic density measured using 18 F-SynVesT-1, a fluorine 18 ( 18 F)-labeled radiotracer, brain PET and to explore the independent associations between these markers and synaptic density. Materials and Methods This prospective study included 50 cognitively unimpaired (mean age, 65.0 years ± 8.3 [SD]; 37 female) participants and 70 participants with cognitive impairment (mean age, 69.5 years ± 7.9; 43 female) from the Memory Clinic of Shanghai Jiao Tong University Affiliated Ruijin Hospital and communities in Shanghai. Amyloid-β (Aβ) and tau were assessed using 18 F-florbetapir and 18 F-MK6240 PET/CT. Synaptic density was evaluated with 18 F-SynVesT-1 PET/MRI. Pearson correlation analysis was used to investigate relationships of plasma (Aβ42/40 ratio, phosphorylated tau 181 [p-tau-181], glial fibrillary acid protein [GFAP], neurofilament light) and serum (C-reactive protein, tumor necrosis factor-α, α-synuclein, neurogranin, active plasminogen activator inhibitor-1, tissue plasminogen activator) biomarkers with synaptic density. Linear regression models and mediation analysis were used to explore effects of other AD-related pathologies on these relationships. Results Correlations were observed between increased p-tau-181 and GFAP and decreased synaptic density in global cortex ( r p-tau-181 = -0.352, r GFAP = -0.386; both P < .001) and hippocampus ( r p-tau-181 = -0.361, r GFAP = -0.369; both P < .001) at 18 F-SynVesT-1 PET/MRI. The relationships between p-tau-181 and GFAP with 18 F-SynVesT-1 PET/MRI persisted after controlling for plasma Aβ42/40 ratio, Aβ PET, or cortical thickness ( P value range, <.001-.01). This association disappeared after controlling for tau PET ( P value range, .08-.83). Conclusion Plasma p-tau-181 and GFAP are closely associated with synaptic density measured using 18 F-SynVesT-1 PET/MRI, with the relationship primarily influenced by tau accumulation rather than Aβ deposition or cortical thickness. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Giannakopoulos in this issue.

Background: Tractography based on diffusion MRI (dMRI) is a useful tool to study white matter of the developing brain. However, its application in fetal brains is limited due to motion artifacts and low resolution of in utero dMRI, leading to reduced reliability, which was scarcely investigated in previous studies., Purpose: To identify reliably traceable fibers in fetal brains and assess whether reproducibility varies with gestational age (GA) and varies between brain regions., Study Type: Prospective cohort study., Subjects: A total of 44 healthy fetuses with GAs between 25 and 37 (31 ± 6)., Field Strength/sequence: 3-T, diffusion-weighted echo-planar imaging sequence (2-5 repeated dMRI scans within the same session per subject)., Assessment: We fitted dMRI with constrained spherical deconvolution model and conducted tractography on eight fibers. We extracted volume, fractional anisotropy, and fiber count for each fiber and assessed the reproducibility of these metrics between repeated scans within each subject. Data were divided into two age-based subgroups (≤30 weeks, N = 28, and >30 weeks, N = 16) for further tests., Statistical Tests: The reproducibility were compared between fibers by analysis of variance and two-sample t tests. Multiple comparisons were corrected by the false discovery rate (5% was accepted)., Results: The reproducibility of the anterior thalamic radiation, inferior longitudinal fasciculus (ILF), genu of the corpus callosum (GCC), and body of the corpus callosum (BCC) significantly decreased with advancing GA (correlation coefficient = 0.525-0.823), as confirmed by group comparisons between fetuses in early GA (≤30 weeks) and late GA (>30 weeks) groups. Corticospinal tract, inferior fronto-occipital fasciculus, and GCC showed high reproducibility for fiber count (weighted dice average = 0.846 vs. 0.814), while BCC and ILF exhibited the lowest reproducibility in both age groups., Data Conclusion: The study indicates that the reliability of fetal brain tractography depends on GA and varies among different fibers., Level of Evidence: 2 TECHNICAL EFFICACY: Stage 2., (© 2024 International Society for Magnetic Resonance in Medicine.)

Background: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β and tau proteins, leading to neurofibrillary tangles. A biomarker-based diagnostic method called the ATN system categorizes AD pathology into amyloid-β (A), tau (T), and neurodegeneration (N). The relationship between regional tau deposition and reduced glucose metabolism in the preclinical AD stage is not well understood., Objective: We presented voxel-by-voxel metabolic/tau deposition ratio (MTR) images to investigate the effects of tau deposition on metabolism in AD brains on a stage-by-stage basis., Methods: We selected 174 subjects who underwent 3D-MRI, FDG-PET, amyloid PET, and tau PET scans. MTR images were created by normalizing FDG-PET toMK6240 PET images. Voxel-wise comparisons among 63 cognitively normal amyloid-negative (CNA) subjects, 49 subjects with AD dementia (ADD), 23 subjects with mild cognitive impairment due to AD (MCA), and 39 preclinical AD (PRC) subjects were conducted., Results: There was reduced glucose metabolism in ADD and MCA groups compared to CNA, predominantly in parietotemporal areas. Tau deposition was observed in wider areas in ADD and restricted to the medial temporal lobes in MCA. MTR exhibited significant reductions in broader regions in ADD and MCA, indicating simultaneous glucose metabolism decrease and tau deposition. At the MCA and PRC stages, glucose metabolism impairment and tau deposition were shown in separate regions by FDG PET and tau PET, respectively, while MTR images showed impairment in both regions., Conclusions: Our findings suggest that MTR imaging provides insights into AD pathophysiology by simultaneously assessing glucose metabolism and tau deposition. In the early stage of the AD continuum (MCA and PRC), metabolic decline and tau deposition occur independently in different brain regions., Competing Interests: Declaration of conflicting interestsKazunari Ishii received lecture fees from Nihon Medi-physics Co., Ltd.

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Brain microvascular dysfunction is an important feature of Alzheimer's disease (AD). To better understand the brain microvascular molecular signatures of AD, we processed and analyzed isolated human brain microvessels by data-independent acquisition liquid chromatography with tandem mass spectrometry (DIA LC-MS/MS) to generate a quantitative dataset at the peptide and protein level. Brain microvessels were isolated from parietal cortex grey matter using protocols that preserve viability for downstream functional studies. Our cohort included 23 subjects with clinical and neuropathologic concordance for Alzheimer's disease, and 21 age-matched controls. In our analysis, we identified 168 proteins whose abundance was significantly increased, and no proteins that were significantly decreased in AD. The most highly increased proteins included amyloid beta, tau, midkine, SPARC related modular calcium binding 1 (SMOC1), and fatty acid binding protein 7 (FABP7). Additionally, Gene Ontology (GO) enrichment analysis identified the enrichment of increased proteins involved in cellular detoxification and antioxidative responses. A systematic evaluation of protein functions using the UniProt database identified groupings into common functional themes including the regulation of cellular proliferation, cellular differentiation and survival, inflammation, extracellular matrix, cell stress responses, metabolism, coagulation and heme breakdown, protein degradation, cytoskeleton, subcellular trafficking, cell motility, and cell signaling. This suggests that AD brain microvessels exist in a stressed state of increased energy demand, and mount a compensatory response to ongoing oxidative and cellular damage that is associated with AD. We also used public RNAseq databases to identify cell-type enriched genes that were detected at the protein level and found no changes in abundance of these proteins between control and AD groups, indicating that changes in cellular composition of the isolated microvessels were minimal between AD and no-AD groups. Using public data, we additionally found that under half of the proteins that were significantly increased in AD microvessels had concordant changes in brain microvascular mRNA, implying substantial discordance between gene and protein levels. Together, our results offer novel insights into the molecular underpinnings of brain microvascular dysfunction in AD., (© 2024. The Author(s).)

Neurodegenerative diseases are characterized by the abnormal filamentous assembly of specific proteins in the central nervous system 1 . Human genetic studies have established a causal role for protein assembly in neurodegeneration 2 . However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in cryo-electron microscopy have enabled the structures of the protein filaments to be determined from the brains of patients 1 . All neurodegenerative diseases studied to date have been characterized by the self-assembly of proteins in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) types A and B 3,4 . Here we used cryo-electron microscopy to determine filament structures from the brains of individuals with FTLD-TDP type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/G284-N345 and ANXA11 residues L39-Y74 from their respective low-complexity domains. Regions of TDP-43 and ANXA11  that were previously implicated in protein-protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as an approximately 22 kDa N-terminal fragment lacking the annexin core domain. Immunohistochemistry of brain sections showed the colocalization of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP type C. This work establishes a central role for ANXA11 in FTLD-TDP type C. The unprecedented formation of heteromeric amyloid filaments in the human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases., (© 2024. Crown.)

The black box nature of deep neural networks (DNNs) makes researchers and clinicians hesitant to rely on their findings. Saliency maps can enhance DNN explainability by suggesting the anatomic localization of relevant brain features. This study compares seven popular attribution-based saliency approaches to assign neuroanatomic interpretability to DNNs that estimate biological brain age (BA) from magnetic resonance imaging (MRI). Cognitively normal (CN) adults (N = 13,394, 5,900 males; mean age: 65.82 ± 8.89 years) are included for DNN training, testing, validation, and saliency map generation to estimate BA. To study saliency robustness to the presence of anatomic deviations from normality, saliency maps are also generated for adults with mild traumatic brain injury (mTBI, N = 214, 135 males; mean age: 55.3 ± 9.9 years). We assess saliency methods' capacities to capture known anatomic features of brain aging and compare them to a surrogate ground truth whose anatomic saliency is known a priori. Anatomic aging features are identified most reliably by the integrated gradients method, which outperforms all others through its ability to localize relevant anatomic features. Gradient Shapley additive explanations, input × gradient, and masked gradient perform less consistently but still highlight ubiquitous neuroanatomic features of aging (ventricle dilation, hippocampal atrophy, sulcal widening). Saliency methods involving gradient saliency, guided backpropagation, and guided gradient-weight class attribution mapping localize saliency outside the brain, which is undesirable. Our research suggests the relative tradeoffs of saliency methods to interpret DNN findings during BA estimation in typical aging and after mTBI., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: A number of peptide incretin receptor agonists (IRAs) show promise as therapeutics for Alzheimer's disease (AD) and Parkinson's disease (PD). Transport across the blood-brain barrier (BBB) is one way for IRAs to act directly within the brain. To determine which IRAs are high priority candidates for treating these disorders, we have studied their brain uptake pharmacokinetics., Methods: We quantitatively measure the ability of four IRAs to cross the BBB. We injected adult male CD-1 mice intravenously with 125 I- or 14 C-labeled albiglutide, dulaglutide, DA5-CH, or tirzepatide and used multiple-time regression analyses to measure brain kinetics up to 1 hour. For those IRAs failing to enter the brain 1 h after intravenous injection, we also investigated their ability to enter over a longer time frame (i.e., 6 h)., Results: Albiglutide and dulaglutide had the fastest brain uptake rates within 1 hour. DA5-CH appears to enter the brain rapidly, reaching equilibrium quickly. Tirzepatide does not appear to cross the BBB within 1 h after iv injection but like albumin, did so slowly over 6 h, presumably via the extracellular pathways., Conclusions: We find that IRAs can cross the BBB by two separate processes; one that is fast and one that is slow. Three of the four IRAs investigated here have fast rates of transport and should be taken into consideration for testing as AD and PD therapeutics as they would have the ability to act quickly and directly on the brain as a whole.

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., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Using Phosphorus Magnetic Resonance Spectroscopy ( 31 P MRS), we examined five metabolites associated with brain energy cycle, and cellular membrane production and degradation in 11 brain regions of 48 children (age 6-15), and 80 middle-aged and older adults (age 52-87). Levels of phosphomonoesters (PMEs) and phosphodiesters (PDEs), gamma plus alpha adenosine triphosphate (γαATP), phosphocreatine (PCr) and inorganic phosphate (Pi), were residualized on the total amplitude value. PMEs were greater in children compared to adults, whereas PDEs showed the opposite age difference. Higher γαATP and lower Pi were found in children compared to adults. The age group differences were particularly salient in the association cortices and anterior white matter. Among children, age correlated negatively with PMEs and positively with PDEs in association cortices. Compared to children, adults had lower intracellular pH. The results suggest reduction in membrane synthesis and increase in membrane degradation in adolescents and to a greater degree in adults compared to younger children. Concomitant reduction in γαATP and increase in Pi are consistent with reduced energy consumption in adolescents and further drop in middle-aged and older adults, although it is impossible to distinguish declines in energy supply from reduced demand due to shrinking neuropil, without longitudinal studies., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

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., (© 2024. The Author(s).)

Introduction: Microtubule (MT) stability is crucial for proper neuronal function. Understanding MT dysregulation is critical for connecting amyloid beta (Aβ) and tau-based degenerative events and early changes in presymptomatic Alzheimer's disease (AD). Herein we present positron emission tomography (PET) imaging properties of our MT-PET radiotracer, [ 11 C]MPC-6827, in multiple established AD mouse models., Methods: Longitudinal PET, biodistribution, autoradiography, immunohistochemistry, and behavioral studies were conducted at multiple time points in APPswe/PSEN1dE9 (APP/PS1), P301S-PS19 (P301S), 5xFAD, and age-matched control mice., Results: Longitudinal [ 11 C]MPC-6827 brain imaging showed significant increases in APP/PS1, P301S, and 5xFAD mice compared to controls. Longitudinal MT-PET correlated positively with biodistribution, autoradiography, and immunohistochemistry results and negatively with behavior data., Discussion: Our study demonstrated significant longitudinal [ 11 C]MPC-6827 PET increases in multiple AD mouse models for the first time. Strong correlations between PET and biomarker data underscored the interplay of MT destabilization, amyloid, and tau pathology in AD. These results suggest [ 11 C]MPC-6827 PET as a promising tool for monitoring MT dysregulation early in AD progression., Highlights: Longitudinal positron emission tomography (PET) imaging studies using [ 11 C]MPC-6827 in multiple established Alzheimer's disease (AD) mouse models revealed an early onset of microtubule dysregulation, with significant changes in brain radiotracer uptake evident from 2 to 4 months of age. Intra-group analysis showed a progressive increase in microtubule dysregulation with increasing AD burden, supported by significant correlations between PET imaging data and biodistribution, autoradiography, and molecular pathological markers. [ 11 C]MPC-6827 PET imaging demonstrated its efficacy in detecting early microtubule alterations preceding observable behavioral changes in AD mouse models, suggesting its potential for early AD imaging. The inclusion of the 5xFAD mouse model further elucidated the impact of amyloid beta (Aβ) toxicity on inducing tau hyperphosphorylation-mediated microtubule dysregulation, highlighting the versatility of [ 11 C]MPC-6827 in delineating various aspects of AD pathology. Our study provides immediate clarity on high uptake of the microtubule-based radiotracer in AD brains in a longitudinal setting, which directly informs clinical utility in Aβ/tau-based studies., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Importance: Alzheimer's disease (AD) is the most common cause of dementia in the elderly with the incidence rising exponentially after the age of 65 years. Unfortunately, effective treatments are extremely limited and definite diagnosis can only be made at autopsy. This is in part due to our limited understanding of the complex pathophysiology, including the various genetic, environmental, and metabolic contributing factors. In an effort to better understand this complex disease, researchers have employed nonhuman primates as translational models., Case Presentation: This report aims to describe the AD-like neuropathology in the brain of a 37-year-old female baboon ( Papio hamadryas ), which at the time of her death made her the oldest hamadryas baboon at any member institution of the Association of Zoos and Aquariums. A diagnostic necropsy was performed, and the brain was evaluated for neurodegenerative disease. Frequent amyloid-β deposits were identified, consistent with what has been described in other geriatric nonhuman primates. Phospho-tau pathology, including neurofibrillary tangles, a feature not well-described in other primate models, was also abundant., Conclusions and Relevance: Our results suggest that more detailed, prospective, longitudinal studies are warranted utilizing this particular species to see if they represent a viable model for human brain aging., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Korean Society of Veterinary Science.)

Machine learning can be used to create "biologic clocks" that predict age. However, organs, tissues, and biofluids may age at different rates from the organism as a whole. We sought to understand how cerebrospinal fluid (CSF) changes with age to inform the development of brain aging-related disease mechanisms and identify potential anti-aging therapeutic targets. Several epigenetic clocks exist based on plasma and neuronal tissues; however, plasma may not reflect brain aging specifically and tissue-based clocks require samples that are difficult to obtain from living participants. To address these problems, we developed a machine learning clock that uses CSF proteomics to predict the chronological age of individuals with a 0.79 Pearson correlation and mean estimated error (MAE) of 4.30 years in our validation cohort. Additionally, we analyzed proteins highly weighted by the algorithm to gain insights into changes in CSF and uncover novel insights into brain aging. We also demonstrate a novel method to create a minimal protein clock that uses just 109 protein features from the original clock to achieve a similar accuracy (0.75 correlation, MAE 5.41). Finally, we demonstrate that our clock identifies novel proteins that are highly predictive of age in interactions with other proteins, but do not directly correlate with chronological age themselves. In conclusion, we propose that our CSF protein aging clock can identify novel proteins that influence the rate of aging of the central nervous system (CNS), in a manner that would not be identifiable by examining their individual relationships with age., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Calorie restriction (CR) is a robust intervention that can slow biological aging and extend lifespan. In the brain, terminally differentiated neurons and glia accumulate oxidative damage with age, reducing their optimal function. We investigated if CR could reduce oxidative DNA damage to white matter oligodendrocytes and microglia. This study utilized post-mortem brain tissue from rhesus monkeys that died after decades on a 30 % reduced calorie diet. We found that CR subjects had significantly fewer cells with oxidative damage within the corpus callosum and the cingulum bundle. Oligodendrocytes specifically showed the greatest response to CR with a robust reduction in DNA damage. Additionally, we observed alterations in microglia morphology with CR subjects having a higher proportion of ramified, homeostatic microglia and fewer pro-inflammatory, hypertrophic microglia relative to controls. Furthermore, we determined that the observed attenuation in damaged DNA occurs primarily within mitochondria. Overall, these data suggest that long-term CR can reduce oxidative DNA damage and offer a neuroprotective effect in a cell-type-specific manner in the aging monkey brain., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflicts of interest, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Infections have been associated with the incidence of Alzheimer disease and related dementias, but the mechanisms responsible for these associations remain unclear. Using a multicohort approach, we found that influenza, viral, respiratory, and skin and subcutaneous infections were associated with increased long-term dementia risk. These infections were also associated with region-specific brain volume loss, most commonly in the temporal lobe. We identified 260 out of 942 immunologically relevant proteins in plasma that were differentially expressed in individuals with an infection history. Of the infection-related proteins, 35 predicted volumetric changes in brain regions vulnerable to infection-specific atrophy. Several of these proteins, including PIK3CG, PACSIN2, and PRKCB, were related to cognitive decline and plasma biomarkers of dementia (Aβ 42/40 , GFAP, NfL, pTau-181). Genetic variants that influenced expression of immunologically relevant infection-related proteins, including ITGB6 and TLR5, predicted brain volume loss. Our findings support the role of infections in dementia risk and identify molecular mediators by which infections may contribute to neurodegeneration., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Diet may promote brain health in metabolically impaired older individuals. In an 8-week randomized clinical trial involving 40 cognitively intact older adults with insulin resistance, we examined the effects of 5:2 intermittent fasting and the healthy living diet on brain health. Although intermittent fasting induced greater weight loss, the two diets had comparable effects in improving insulin signaling biomarkers in neuron-derived extracellular vesicles, decreasing the brain-age-gap estimate (reflecting the pace of biological aging of the brain) on magnetic resonance imaging, reducing brain glucose on magnetic resonance spectroscopy, and improving blood biomarkers of carbohydrate and lipid metabolism, with minimal changes in cerebrospinal fluid biomarkers for Alzheimer's disease. Intermittent fasting and healthy living improved executive function and memory, with intermittent fasting benefiting more certain cognitive measures. In exploratory analyses, sex, body mass index, and apolipoprotein E and SLC16A7 genotypes modulated diet effects. The study provides a blueprint for assessing brain effects of dietary interventions and motivates further research on intermittent fasting and continuous diets for brain health optimization. For further information, please see ClinicalTrials.gov registration: NCT02460783., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Type 2 diabetes mellitus (T2DM) is common and increasing in prevalence worldwide, with devastating public health consequences. While peripheral insulin resistance is a key feature of most forms of T2DM and has been investigated for over a century, research on brain insulin resistance (BIR) has more recently been developed, including in the context of T2DM and non-diabetes states. Recent data support the presence of BIR in the aging brain, even in non-diabetes states, and found that BIR may be a feature in Alzheimer's disease (AD) and contributes to cognitive impairment. Further, therapies used to treat T2DM are now being investigated in the context of AD treatment and prevention, including insulin. In this review, we offer a definition of BIR, and present evidence for BIR in AD; we discuss the expression, function, and activation of the insulin receptor (INSR) in the brain; how BIR could develop; tools to study BIR; how BIR correlates with current AD hallmarks; and regional/cellular involvement of BIR. We close with a discussion on resilience to both BIR and AD, how current tools can be improved to better understand BIR, and future avenues for research. Overall, this review and position paper highlights BIR as a plausible therapeutic target for the prevention of cognitive decline and dementia due to AD.

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 (β 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., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Targeting brain insulin resistance (BIR) has become an attractive alternative to traditional therapeutic treatments for Alzheimer's disease (AD). Incretin receptor agonists (IRAs), targeting either or both of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, have proven to reverse BIR and improve cognition in mouse models of AD. We previously showed that many, but not all, IRAs can cross the blood-brain barrier (BBB) after intravenous (IV) delivery. Here we determined if widespread brain uptake of IRAs could be achieved by circumventing the BBB using intranasal (IN) delivery, which has the added advantage of minimizing adverse gastrointestinal effects of systemically delivered IRAs. Of the 5 radiolabeled IRAs tested (exenatide, dulaglutide, semaglutide, DA4-JC, and DA5-CH) in CD-1 mice, exenatide, dulaglutide, and DA4-JC were successfully distributed throughout the brain following IN delivery. We observed significant sex differences in uptake for DA4-JC. Dulaglutide and DA4-JC exhibited high uptake by the hippocampus and multiple neocortical areas. We further tested and found the presence of AD-associated Aβ pathology minimally affected uptake of dulaglutide and DA4-JC. Of the 5 tested IRAs, dulaglutide and DA4-JC are best capable of accessing brain regions most vulnerable in AD (neocortex and hippocampus) after IN administration. Future studies will need to be performed to determine if IN IRA delivery can reduce BIR in AD or animal models of that disorder., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: The physical function of elderly individuals reflects whether they have had a history of regular physical activity over the long term. Such indicators have been found to have a certain connection with cognitive function these years. However, there is limited research that associates it with mechanisms such as cerebral Aβ deposition. We aim to investigate this relationship and unveil the underlying mechanisms., Method: Physical function and cognition data of 4189 participants were obtained from the Chinese preclinical Alzheimer's disease study. Participants were divided into six groups according to disease severity. Among them, 1048 participants underwent the positron emission tomography-computed tomography (PET-CT) and plasma biomarker test. Grip strength and gait were combined into a score indicating physical function. Multiple linear regression models and logistic regression models were mainly used to conduct the analysis., Results: There was a significant positive correlation between physical function and cognitive function (R = 0.48, p < 0.001), independent of sex, age, apolipoprotein E-ε4 genotype, and disease stages (p < 0.001). Physical function was effective in distinguishing individuals with cognitive impairment from those without (AUC = 0.835). Physical function was negatively associated with brain Aβ deposition (p = 0.008) and brain Aβ had an intermediary effect (p < 0.01) on the association between physical function and cognition in women. This association was mainly evident in the lateral parietal, lateral temporal, posterior cingulate, frontal, occipital, and precuneus regions. Physical function was negatively associated with plasma neurofilament light-chain (Nfl) level (p < 0.001)., Conclusions: Physical function is strongly associated with cognitive function in the Chinese elderly, and brain Aβ deposition partly mediates the linkage in women. Plasma Nfl can be used as a potential target for exercise intervention in cognitive function. Improving physical function will contribute to the alleviation of cognition decline., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Little is known about changes in the brain associated with frailty, in particular, which brain areas could be related to frailty in older people without cognitive impairment. This scoping review mapped evidence on functional and/or structural brain changes in frail older adults without cognitive impairment. The methodology proposed by the JBI® was used in this study. The search in PubMed, PubMed PMC, BVS/BIREME, EBSCOHOST, Scopus, Web of Science, Embase, and PROQUEST was conducted up to January 2023. Studies included following the population, concepts, context and the screening and data extraction were performed by two independent reviewers. A total of 9,912 records were identified, 5,676 were duplicates and were excluded. The remaining articles were screened; 31 were read in full and 17 articles were included. The results showed that lesions in white matter hyperintensities, reduced volume of the hippocampus, cerebellum, middle frontal gyrus, low gray matter volume, cortical atrophy, decreased connectivity of the supplementary motor area, presence of amyloid-beta peptide (aβ) in the anterior and posterior putamen and precuneus regions were more frequently observed in frail older adults, compared with non-frail individuals. Studies have suggested that such findings may be of neurodegenerative or cerebrovascular origin. The identification of these brain alterations in frail older adults through neuroimaging studies contributes to our understanding of the underlying mechanisms of frailty. Such findings may have implications for the early detection of frailty and implementation of intervention strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Multidomain interventions have demonstrable benefits for promoting healthy aging, but self-empowerment strategies to sustain long-term gains remain elusive., Objective: This study evaluated the effects of digital somatosensory dance game participation on brain imagery changes as primary outcomes and other physical and mental health measures as secondary outcomes related to healthy aging., Methods: Between August 31, 2020, and June 27, 2021, this randomized controlled trial recruited 60 eligible participants older than 55 years with no recent engagement in digital dance games. A computer-generated randomization sequence was used to allocate participants 1:1, without stratification, to an intervention group (n=30) who underwent digital somatosensory dance game training or a control group (n=30). An anonymized code masked the intervention allocations from the investigators, and individuals who assigned the interventions were not involved in analyzing the study data. The intervention entailed two 30-minute dance game sessions per week for 6 months, and the control group received healthy aging education. Primary outcomes were brain imagery changes. All variables were measured at baseline and the 6-month follow-up, and intervention effects were estimated using t tests with intention-to-treat analyses., Results: Compared with the control group, intervention participants had significantly different brain imagery in the gray matter volume (GMV) of the left putamen (estimate 0.016, 95% CI 0.008 to 0.024; P<.001), GMV of the left pallidum (estimate 0.02, 95% CI 0.006 to 0.034; P=.004), and fractional amplitude of low frequency fluctuations of the left pallidum (estimate 0.262, 95% CI 0.084 to 0.439; P=.004). Additionally, the intervention group had different imagery in the cerebellum VI GMV (estimate 0.011, 95% CI 0.003 to 0.02; P=.01). The intervention group also had improved total Montreal Cognitive Assessment scores (estimate 1.2, 95% CI 0.27 to -2.13; P<.01), quality of life (estimate 7.08, 95% CI 2.35 to 11.82; P=.004), and time spent sitting on weekdays (estimate -1.96, 95% CI -3.33 to -0.60; P=.005). Furthermore, dance performance was significantly associated with cognitive performance (P=.003), health status (P=.14), resilience (P=.007), and demoralization (P<.001)., Conclusions: Digital somatosensory dance game participation for 6 months was associated with brain imagery changes in multiple regions involving somatosensory, motor, visual, and attention functions, which were consistent with phenotypic improvements associated with healthy aging., Trial Registration: ClinicalTrials.gov NCT05411042; https://clinicaltrials.gov/study/NCT05411042., (©Heng-Hsin Tung, Chen-Yuan Kuo, Pei-Lin Lee, Chih-Wen Chang, Kun-Hsien Chou, Ching-Po Lin, Liang-Kung Chen. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 30.07.2024.)

Background: Cerebral microbleeds (CMB) increase the risk for Alzheimer disease. Current neuroimaging methods that are used to detect CMB are costly and not always accessible., Objective: This study aimed to explore whether the digital clock-drawing test (DCT) may provide a behavioral indicator of CMB., Methods: In this study, we analyzed data from participants in the Framingham Heart Study offspring cohort who underwent both brain magnetic resonance imaging scans (Siemens 1.5T, Siemens Healthcare Private Limited; T2*-GRE weighted sequences) for CMB diagnosis and the DCT as a predictor. Additionally, paper-based clock-drawing tests were also collected during the DCT. Individuals with a history of dementia or stroke were excluded. Robust multivariable linear regression models were used to examine the association between DCT facet scores with CMB prevalence, adjusting for relevant covariates. Receiver operating characteristic (ROC) curve analyses were used to evaluate DCT facet scores as predictors of CMB prevalence. Sensitivity analyses were conducted by further including participants with stroke and dementia., Results: The study sample consisted of 1020 (n=585, 57.35% female) individuals aged 45 years and older (mean 72, SD 7.9 years). Among them, 64 (6.27%) participants exhibited CMB, comprising 46 with lobar-only, 11 with deep-only, and 7 with mixed (lobar+deep) CMB. Individuals with CMB tended to be older and had a higher prevalence of mild cognitive impairment and higher white matter hyperintensities compared to those without CMB (P<.05). While CMB were not associated with the paper-based clock-drawing test, participants with CMB had a lower overall DCT score (CMB: mean 68, SD 23 vs non-CMB: mean 76, SD 20; P=.009) in the univariate comparison. In the robust multiple regression model adjusted for covariates, deep CMB were significantly associated with lower scores on the drawing efficiency (β=-0.65, 95% CI -1.15 to -0.15; P=.01) and simple motor (β=-0.86, 95% CI -1.43 to -0.30; P=.003) domains of the command DCT. In the ROC curve analysis, DCT facets discriminated between no CMB and the CMB subtypes. The area under the ROC curve was 0.76 (95% CI 0.69-0.83) for lobar CMB, 0.88 (95% CI 0.78-0.98) for deep CMB, and 0.98 (95% CI 0.96-1.00) for mixed CMB, where the area under the ROC curve value nearing 1 indicated an accurate model., Conclusions: The study indicates a significant association between CMB, especially deep and mixed types, and reduced performance in drawing efficiency and motor skills as assessed by the DCT. This highlights the potential of the DCT for early detection of CMB and their subtypes, providing a reliable alternative for cognitive assessment and making it a valuable tool for primary care screening before neuroimaging referral., (©Samia C Akhter-Khan, Qiushan Tao, Ting Fang Alvin Ang, Cody Karjadi, Indira Swetha Itchapurapu, David J Libon, Michael Alosco, Jesse Mez, Wei Qiao Qiu, Rhoda Au. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 29.07.2024.)

Psychosocial experiences affect brain health and aging trajectories, but the molecular pathways underlying these associations remain unclear. Normal brain function relies on energy transformation by mitochondria oxidative phosphorylation (OxPhos). Two main lines of evidence position mitochondria both as targets and drivers of psychosocial experiences. On the one hand, chronic stress exposure and mood states may alter multiple aspects of mitochondrial biology; on the other hand, functional variations in mitochondrial OxPhos capacity may alter social behavior, stress reactivity, and mood. But are psychosocial exposures and subjective experiences linked to mitochondrial biology in the human brain? By combining longitudinal antemortem assessments of psychosocial factors with postmortem brain (dorsolateral prefrontal cortex) proteomics in older adults, we find that higher well-being is linked to greater abundance of the mitochondrial OxPhos machinery, whereas higher negative mood is linked to lower OxPhos protein content. Combined, positive and negative psychosocial factors explained 18 to 25% of the variance in the abundance of OxPhos complex I, the primary biochemical entry point that energizes brain mitochondria. Moreover, interrogating mitochondrial psychobiological associations in specific neuronal and nonneuronal brain cells with single-nucleus RNA sequencing (RNA-seq) revealed strong cell-type-specific associations for positive psychosocial experiences and mitochondria in glia but opposite associations in neurons. As a result, these "mind-mitochondria" associations were masked in bulk RNA-seq, highlighting the likely underestimation of true psychobiological effect sizes in bulk brain tissues. Thus, self-reported psychosocial experiences are linked to human brain mitochondrial phenotypes., Competing Interests: Competing interests statement:The authors declare no competing interest.

Intracranial volume (ICV) reflects maximal brain development and is associated with later-life cognitive abilities. We quantified ICV among first- and second-generation Hispanic and Latino adults from the Study of Latinos-Investigation of Cognitive Aging - MRI (SOL-INCA-MRI), estimated ICV heritability, and tested its associations with previously reported genetic variants, both individually and as a genetic risk score (GRS). We also estimated the association of ICV with early life environmental measures: nativity or age of immigration and parental education. The estimated heritability of ICV was 19% (95% CI, 0.1%-56%) in n=1781 unrelated SOL-INCA-MRI individuals. Four of 10 tested genetic variants were associated with ICV and an increase of 1 SD of the ICV-GRS was associated with an increase of 10.37 cm 3 in the ICV (95% CI, 5.29-15.45). Compared to being born in the continental United States, immigrating to the United States at age 11 years or older was associated with 24 cm 3 smaller ICV (95% CI, -39.97 to -8.06). Compared to both parents having less than high-school education, at least 1 parent completing high-school education was associated with 15.4 cm 3 greater ICV (95% CI, 4.46-26.39). These data confirm the importance of early life health on brain development., Competing Interests: Conflict of InterestNo conflict of interest reported by authors.

Gray matter (GM) alterations play a role in aging-related disorders like Alzheimer's disease and related dementias, yet MRI studies mainly focus on macroscopic changes. Although reliable indicators of atrophy, morphological metrics like cortical thickness lack the sensitivity to detect early changes preceding visible atrophy. Our study aimed at exploring the potential of diffusion MRI in unveiling sensitive markers of cortical and subcortical age-related microstructural changes and assessing their associations with cognitive and behavioral deficits. We leveraged the Human Connectome Project-Aging cohort that included 707 participants (394 female; median age = 58, range = 36-90 years) and applied the powerful mean apparent diffusion propagator model to measure microstructural parameters, along with comprehensive behavioral and cognitive test scores. Both macro- and microstructural GM characteristics were strongly associated with age, with widespread significant microstructural correlations reflective of cellular morphological changes, reduced cellular density, increased extracellular volume, and increased membrane permeability. Importantly, when correlating MRI and cognitive test scores, our findings revealed no link between macrostructural volumetric changes and neurobehavioral performance. However, we found that cellular and extracellular alterations in cortical and subcortical GM regions were associated with neurobehavioral performance. Based on these findings, it is hypothesized that increased microstructural heterogeneity and decreased neurite orientation dispersion precede macrostructural changes, and that they play an important role in subsequent cognitive decline. These alterations are suggested to be early markers of neurocognitive performance that may distinctly aid in identifying the mechanisms underlying phenotypic aging and subsequent age-related functional decline., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)