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BackgroundStudies have investigated white matter microstructure in relation to late-life cognitive impairments, with fractional anisotropy (FA) and mean diffusivity (MD) measures thought to capture demyelination and axonal degradation. However, new post-processing methods allow isolation of free water (FW), which captures extracellular fluid contributions such as atrophy and neuroinflammation, from tissue components. FW also appears to be highly relevant to late-life cognitive impairment. Here, we evaluated whether executive functions are associated with FW, and FA and MD corrected for FW (FAFWcorr and MDFWcorr).MethodWe examined 489 non-demented men in the Vietnam Era Twin Study of Aging (VETSA) at mean age 68. Two latent factors capturing 'common executive function' and 'working-memory specific' processes were estimated based on 6 tasks. Analyses focused on 11 cortical white matter tracts across three metrics: FW, FAFWcorr, and MDFWcorr.ResultsBetter 'common executive function' was associated with lower FW across 9 of the 11 tracts. There were no significant associations with intracellular metrics after false discovery rate correction. Effects also appeared driven by individuals with MCI (13.7% of the sample). Working memory-specific tasks showed some associations with FAFWcorr, including the triangularis portion of the inferior frontal gyrus. There was no evidence that cognitive reserve (i.e., general cognitive ability assessed in early adulthood) moderated these associations between executive function and FW or FA.DiscussionExecutive function abilities in early old age are associated primarily with extracellular fluid (FW) as opposed to white matter (FAFWcorr or MDFWcorr). Moderation analyses suggested cognitive reserve does not play a strong role in these associations, at least in this sample of non-demented men.

Introduction: It is unclear how rates of white matter microstructural decline differ between normal aging and abnormal aging. Methods: Diffusion MRI data from several well‐established longitudinal cohorts of aging (Alzheimer's Disease Neuroimaging Initiative [ADNI], Baltimore Longitudinal Study of Aging [BLSA], Vanderbilt Memory & Aging Project [VMAP]) were free‐water corrected and harmonized. This dataset included 1723 participants (age at baseline: 72.8 ± 8.87 years, 49.5% male) and 4605 imaging sessions (follow‐up time: 2.97 ± 2.09 years, follow‐up range: 1–13 years, mean number of visits: 4.42 ± 1.98). Differences in white matter microstructural decline in normal and abnormal agers was assessed. Results: While we found a global decline in white matter in normal/abnormal aging, we found that several white matter tracts (e.g., cingulum bundle) were vulnerable to abnormal aging. Conclusions: There is a prevalent role of white matter microstructural decline in aging, and future large‐scale studies in this area may further refine our understanding of the underlying neurodegenerative processes. HIGHLIGHTS: Longitudinal data were free‐water corrected and harmonized.Global effects of white matter decline were seen in normal and abnormal aging.The free‐water metric was most vulnerable to abnormal aging.Cingulum free‐water was the most vulnerable to abnormal aging. [ABSTRACT FROM AUTHOR]

Introduction: White matter microstructure may be abnormal along the Alzheimer's disease (AD) continuum. Methods: Diffusion magnetic resonance imaging (dMRI) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 627), Baltimore Longitudinal Study of Aging (BLSA, n = 684), and Vanderbilt Memory & Aging Project (VMAP, n = 296) cohorts were free‐water (FW) corrected and conventional, and FW‐corrected microstructural metrics were quantified within 48 white matter tracts. Microstructural values were subsequently harmonized using the Longitudinal ComBat technique and inputted as independent variables to predict diagnosis (cognitively unimpaired [CU], mild cognitive impairment [MCI], AD). Models were adjusted for age, sex, race/ethnicity, education, apolipoprotein E (APOE) ε4 carrier status, and APOE ε2 carrier status. Results: Conventional dMRI metrics were associated globally with diagnostic status; following FW correction, the FW metric itself exhibited global associations with diagnostic status, but intracellular metric associations were diminished. Discussion: White matter microstructure is altered along the AD continuum. FW correction may provide further understanding of the white matter neurodegenerative process in AD. Highlights: Longitudinal ComBat successfully harmonized large‐scale diffusion magnetic resonance imaging (dMRI) metrics.Conventional dMRI metrics were globally sensitive to diagnostic status.Free‐water (FW) correction mitigated intracellular associations with diagnostic status.The FW metric itself was globally sensitive to diagnostic status. Multivariate conventional and FW‐corrected models may provide complementary information. [ABSTRACT FROM AUTHOR]

Background: Sex differences in gray matter alterations in aging and AD have been reported, but there have been few large‐scale studies evaluating white matter microstructure. The goal of this study is to leverage multi‐site harmonized diffusion MRI data in tandem with free‐water (FW) imaging to determine the association between sex and white matter microstructure in aging and AD. Method: The dataset used in this study leveraged cross‐sectional data from several cohorts of aging [Alzheimer's Neuroimaging Initiative (ADNI), Baltimore Longitudinal Study of Aging (BLSA), Vanderbilt Memory & Aging Project (VMAP)]. This dataset included 1,898 participants (72±9 years, 59% female). Data was processed using standard preprocessing techniques and followed up with FW postprocessing. FW and FW‐corrected intracellular metrics of fractional anisotropy (FAT), radial diffusivity (RDT), and axial diffusivity (ADT) were then quantified within seven white matter tractography templates (see Figure 1A) and harmonized using the ComBat technique. The sex differences for each microstructural metric were then determined using a linear regression model covarying for age, diagnosis, education, and APOE‐ε4 carrier status. Secondary analyses were conducted to determine sex x diagnosis interactions on white matter microstructure. Result: While we found no sex differences in FW, there were significant associations in all intracellular metrics. Females had significantly lower FAT in the association (pFDR=6.62x10‐10), limbic (pFDR=5.28x10‐9), motor transcallosal (TC) (pFDR=0.008), prefrontal TC (pFDR=6.34x10‐6), and projection (pFDR=4.74x10‐20) tracts and significantly lower ADT in the association (pFDR=5.23x10‐10), limbic (pFDR=1.84x10‐6), prefrontal TC (pFDR=4.41x10‐11), and projection (pFDR=5.29x10‐17) tracts. For RDT, females exhibited higher RDT in all tracts (pFDR range: 4.94x10‐16 – 0.022). Illustrations of these results can be found in Figure 1. Sex differences were compared across cohorts and were similar (Figure 2). The only significant sex x diagnosis interaction was for the projection tract RDT measure (pFDR=0.043, Figure 3). Conclusion: This study suggests intracellular microstructural values (i.e., FAT, ADT, RDT) exhibit strong sex differences, whereby females have lower FAT/ADT and higher RDT compared to males. We also found a sex x diagnosis interaction for projection tract RDT, whereby females with AD exhibited lower RDT, but larger studies with more AD cases would be needed to further explore this finding. [ABSTRACT FROM AUTHOR]

Background: Reduced cerebral blood flow (CBF) is a risk factor for white matter damage. Apolipoprotein E (APOE) e4, a genetic risk factor for Alzheimer's disease and vascular health modifier, is associated with lower CBF. However, it remains unknown if lower CBF is associated with more severe white matter damage among APOE‐e4 carriers. We examine whether associations among regional CBF, cerebrovascular reactivity (CVR), and white matter integrity are modified by APOE‐e4 status in older adults. Method: Vanderbilt Memory and Aging Project participants (n = 313, 73±7 years) underwent 3T brain MRI. Resting grey matter CBF and CVR (CBF response to hypercapnic stimulus, ΔCBF/100*ΔCO2) were quantified in regions of interest from pseudo‐continuous arterial spin labeling (ASL). Fractional anisotropy (FA) was quantified from diffusion tensor imaging in tracts of interest derived from tractography templates. Linear regressions related regional CBF and CVR to tract‐specific FA, adjusting for demographic and vascular variables, regional tissue volume, cognitive status, and APOE‐e4 status. Follow‐up models tested an APOE‐ε4 status x ASL variable interaction term. Result: In main models, lower temporal lobe CBF was associated with lower FA in the occipital lobe, suggesting compromised white matter integrity (p = 0.02). Lower CBF and higher CVR in the occipital lobe were associated with compromised lower FA in all lobes (all p‐values<0.04). Temporal lobe CBF and CVR interacted with APOE‐e4 status, such that lower temporal lobe CBF related to lower FA in the frontal lobe (p = 0.01) and higher temporal lobe CVR related to lower FA in the frontal (p = 0.001) and temporal (p = 0.007) lobes among APOE‐e4 carriers only. Frontal lobe CVR interacted with APOE‐e4 status, such that higher CVR related to lower FA in the frontal (p<0.001) and temporal lobes (p = 0.008) in APOE‐e4 carriers only. Conclusion: Among older adults, APOE‐e4 modifies associations between cerebral hemodynamics and white matter integrity, such that reduced CBF and greater CVR in the temporal lobe are associated with greater white matter damage in APOE‐e4 carriers. APOE‐e4 carriers may be more susceptible to changes in temporal lobe hemodynamics, and vascular changes in the temporal lobe may have a stronger impact on brain health outcomes for carriers compared to non‐carriers. [ABSTRACT FROM AUTHOR]

Background: Several prior studies have used diffusion MRI to investigate the relationship between white matter microstructure and aging; however, many of these studies used conventional diffusion MRI measures and single site data. The goal of the study is to leverage multi‐site harmonized diffusion MRI data in conjunction with a novel post‐processing technique [i.e., free‐water (FW) correction] to quantify the aging related tract‐specific changes in white matter microstructure. Method: The dataset used in this study was collated using several well‐established longitudinal cohorts of aging [Alzheimer's Neuroimaging Initiative (ADNI), Baltimore Longitudinal Study of Aging (BLSA), Vanderbilt Memory & Aging Project (VMAP)]. In total, this dataset included 1,909 participants (mean age at baseline: 72±9 years, 59% female) and 4,844 imaging sessions (mean number of visits: 4 ± 2 years, interval range: 1–12 years). Data was processed using standard approaches and uncorrected fractional anisotropy (FAU) was quantified with seven white matter tractography atlases (see Figure 1A). Data was then post‐processed using the FW correction technique and FW and FW‐corrected FA (FAT) values were quantified. Data were then harmonized using the ComBat technique and linear mixed‐effects regression was conducted on each microstructural measure, covarying for age at baseline, sex, cognitive status, education, APOE‐ε4 carrier status, and APOE‐ε2 carrier status. The effect of aging was modelled using an Age_at_Baseline x Interval interaction term. Result: Age was associated with lower FAU in all seven tracts (pFDR range: 4.77x10‐10 to ‐0.01). In the FW analysis, age was associated with higher FW in all seven tracts (pFDR range: 7.81x10‐12 to 1.33x10‐6). For FAT, however, age was only associated with lower FAT in the limbic tracts (pFDR=0.024) in addition to the occipital (pFDR=1.19x10‐8), parietal (pFDR=2.32x10‐4), and prefrontal (pFDR=0.024) TC tracts. Figure 1B‐D illustrates our findings. Conclusion: This study suggests that while there are global associations with FAU and age, these associations are attenuated once correcting for partial volume effects. Leveraging FW analysis, we found a global association with FW and age, whereby age is associated with higher FW. Further, we found that age is associated with reductions in FAT in the limbic and occipital/parietal/prefrontal TC tracts. [ABSTRACT FROM AUTHOR]

Introduction: The effects of sex, race, and Apolipoprotein E ( APOE ) - Alzheimer's disease (AD) risk factors - on white matter integrity are not well characterized., Methods: Diffusion MRI data from nine well-established longitudinal cohorts of aging were free-water (FW)-corrected and harmonized. This dataset included 4,702 participants (age=73.06 ± 9.75) with 9,671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FA FWcorr ) were used to assess differences in white matter microstructure by sex, race, and APOE -ε4 carrier status., Results: Sex differences in FA FWcorr in association and projection tracts, racial differences in FA FWcorr in projection tracts, and APOE -ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced., Discussion: There are prominent differences in white matter microstructure by sex, race, and APOE -ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted., Competing Interests: SCJ has served on advisory boards for Enigma Biomedical and ALZPath in the past two years. AJS receives support from multiple NIH grants (P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U19 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, U01 AG068057, U01 AG072177, U19 AG074879, and U24 AG074855). He has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor) and participated in Scientific Advisory Boards (Bayer Oncology, Eisai, Novo Nordisk, and Siemens Medical Solutions USA, Inc) and an Observational Study Monitoring Board (MESA, NIH NHLBI), as well as External Advisory Committees for multiple NIA grants. He also serves as Editor-in-Chief of Brain Imaging and Behavior, a Springer-Nature Journal.

The greatest known risk factor for Alzheimer's disease (AD) is age. While both normal aging and AD pathology involve structural changes in the brain, their trajectories of atrophy are not the same. Recent developments in artificial intelligence have encouraged studies to leverage neuroimaging-derived measures and deep learning approaches to predict brain age, which has shown promise as a sensitive biomarker in diagnosing and monitoring AD. However, prior efforts primarily involved structural magnetic resonance imaging and conventional diffusion MRI (dMRI) metrics without accounting for partial volume effects. To address this issue, we post-processed our dMRI scans with an advanced free-water (FW) correction technique to compute distinct FW-corrected fractional anisotropy (FAFWcorr) and FW maps that allow for the separation of tissue from fluid in a scan. We built 3 densely connected neural networks from FW-corrected dMRI, T1-weighted MRI, and combined FW+T1 features, respectively, to predict brain age. We then investigated the relationship of actual age and predicted brain ages with cognition. We found that all models accurately predicted actual age in cognitively unimpaired (CU) controls (FW: r=0.66, p=1.62x10-32; T1: r=0.61, p=1.45x10-26, FW+T1: r=0.77, p=6.48x10-50) and distinguished between CU and mild cognitive impairment participants (FW: p=0.006; T1: p=0.048; FW+T1: p=0.003), with FW+T1-derived age showing best performance. Additionally, all predicted brain age models were significantly associated with cross-sectional cognition (memory, FW: β=-1.094, p=6.32x10-7; T1: β=-1.331, p=6.52x10-7; FW+T1: β=-1.476, p=2.53x10-10; executive function, FW: β=-1.276, p=1.46x10-9; T1: β=-1.337, p=2.52x10-7; FW+T1: β=-1.850, p=3.85x10-17) and longitudinal cognition (memory, FW: β=-0.091, p=4.62x10-11; T1: β=-0.097, p=1.40x10-8; FW+T1: β=-0.101, p=1.35x10-11; executive function, FW: β=-0.125, p=1.20x10-10; T1: β=-0.163, p=4.25x10-12; FW+T1: β=-0.158, p=1.65x10-14). Our findings provide evidence that both T1-weighted MRI and dMRI measures improve brain age prediction and support predicted brain age as a sensitive biomarker of cognition and cognitive decline.

Introduction: It is unclear how rates of white matter microstructural decline differ between normal aging and abnormal aging., Methods: Diffusion MRI data from several well-established longitudinal cohorts of aging (Alzheimer's Disease Neuroimaging Initiative [ADNI], Baltimore Longitudinal Study of Aging [BLSA], Vanderbilt Memory & Aging Project [VMAP]) were free-water corrected and harmonized. This dataset included 1723 participants (age at baseline: 72.8 ± 8.87 years, 49.5% male) and 4605 imaging sessions (follow-up time: 2.97 ± 2.09 years, follow-up range: 1-13 years, mean number of visits: 4.42 ± 1.98). Differences in white matter microstructural decline in normal and abnormal agers was assessed., Results: While we found a global decline in white matter in normal/abnormal aging, we found that several white matter tracts (e.g., cingulum bundle) were vulnerable to abnormal aging., Conclusions: There is a prevalent role of white matter microstructural decline in aging, and future large-scale studies in this area may further refine our understanding of the underlying neurodegenerative processes., Highlights: Longitudinal data were free-water corrected and harmonized.Global effects of white matter decline were seen in normal and abnormal aging.The free-water metric was most vulnerable to abnormal aging.Cingulum free-water was the most vulnerable to abnormal aging., Competing Interests: The authors report no conflicts of interest. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: White matter microstructure may be abnormal along the Alzheimer's disease (AD) continuum., Methods: Diffusion magnetic resonance imaging (dMRI) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n  = 627), Baltimore Longitudinal Study of Aging (BLSA, n  = 684), and Vanderbilt Memory & Aging Project (VMAP, n  = 296) cohorts were free-water (FW) corrected and conventional, and FW-corrected microstructural metrics were quantified within 48 white matter tracts. Microstructural values were subsequently harmonized using the Longitudinal ComBat technique and inputted as independent variables to predict diagnosis (cognitively unimpaired [CU], mild cognitive impairment [MCI], AD). Models were adjusted for age, sex, race/ethnicity, education, apolipoprotein E ( APOE ) ε4 carrier status, and APOE ε2 carrier status., Results: Conventional dMRI metrics were associated globally with diagnostic status; following FW correction, the FW metric itself exhibited global associations with diagnostic status, but intracellular metric associations were diminished., Discussion: White matter microstructure is altered along the AD continuum. FW correction may provide further understanding of the white matter neurodegenerative process in AD., Highlights: Longitudinal ComBat successfully harmonized large-scale diffusion magnetic resonance imaging (dMRI) metrics.Conventional dMRI metrics were globally sensitive to diagnostic status.Free-water (FW) correction mitigated intracellular associations with diagnostic status.The FW metric itself was globally sensitive to diagnostic status. Multivariate conventional and FW-corrected models may provide complementary information., Competing Interests: The authors declare no conflicts of interest. Author disclosures are available in the Supporting Information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)