Although hippocampal volume has served as a long-standing predictor of cognitive decline, diffusion MRI studies of white matter have shown similar relationships. Still, it remains unclear if gray and white matter interact to predict cognitive impairment and longitudinal decline. Here, we investigate whether FW and FW-corrected fractional anisotropy (FA T ) within medial temporal lobe white matter tracts provides meaningful contribution to cognition and cognitive decline beyond hippocampal volume. Using data from the Vanderbilt Memory & Aging Project (n=319), we found that FW was associated with baseline memory and executive function beyond that of hippocampal volume and other comorbidities for memory loss and executive function. Longitudinal analyses demonstrated significant interactions of hippocampal volume and FA T within the inferior longitudinal fasciculus (p=0.043) and cingulum bundle (p=0.025) with decline in memory. For decline in executive function, we found significant interactions on hippocampal volume and FA T within fornix (p=0.025). Results suggest that free-water metrics of white matter have a unique role in cognitive decline and should be include in theoretical models of aging, cerebrovascular disease, and AD.

Highlights RD T within several white matter tracts is associated with SCD. RD T contributes unique variance to SCD beyond that of CSF Aβ 42 . Our findings suggest that RD T is a sensitive marker of SCD.

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.

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Background Blood‐brain barrier (BBB) permeability has been implicated in Alzheimer’s disease and is associated with decreased cerebral blood flow and cognitive impairment. However, associations between BBB permeability and structural brain changes remain unknown. This study relates the cerebrospinal fluid (CSF)/plasma albumin ratio, a proxy measure for BBB permeability, to grey matter volumes and white matter integrity Method Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n=148, 72±6 years, 41% female, 32% apolipoprotein E (APOE) ε4 positive) underwent fasting lumbar puncture for CSF sampling and blood draw for plasma sampling. Participants underwent 3T T1‐weighted imaging to quantify grey matter volumes and diffusion tensor imaging (DTI) to quantify white matter integrity. Voxel‐wise analyses using non‐parametric permutations cross‐sectionally related the CSF/plasma albumin ratio to DTI metrics, adjusting for demographic and health variables, diagnosis, and APOE‐ε4 status. Linear regressions related the CSF/plasma albumin ratio to grey matter volumes, adjusting for identical covariates plus intracranial volume. Follow‐up models tested interactions with APOE‐ε4 status. Result In the entire sample, the CSF/plasma albumin ratio was unrelated to grey matter volumes and white matter integrity (p‐values>0.28) but interacted with APOE‐ε4 status on total grey matter (p‐value=0.02), frontal lobe (p‐value=0.01), and occipital lobe volumes (p‐value=0.04). Stratification suggested a higher CSF/plasma albumin ratio, indicating impaired BBB function, related to smaller grey matter volumes among APOE‐ε4 carriers. The CSF/plasma albumin ratio also interacted with APOE‐ε4 status on white matter integrity in the temporal and frontal lobes (p‐values<0.05), with associations present in APOE‐ε4 non‐carriers. Conclusion Increased BBB permeability is associated with decreased grey matter volume in APOE‐ε4 carriers, specifically in the frontal and occipital lobes. APOE‐ε4 may act as a vascular modifier in these regions, such that increased BBB permeability exacerbates underlying neurotoxicity and neurodegeneration. In contrast, the association between increased BBB permeability and compromised white matter integrity is driven by APOE‐ε4 non‐carriers. Taken together, these results suggest that BBB permeability may be an etiology of neurodegeneration in APOE‐ε4 carriers and highlight the importance of APOE‐ε4 status when studying BBB effects on brain health.

BackgroundSeveral 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.MethodThe 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.ResultAge 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.ConclusionThis 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.

BackgroundCortical surface area, cortical thickness, and hippocampal volume are well‐studied in relation to later life cognitive impairments and AD. Fewer studies have investigated how white mater microstructure relates to cognition in late life. Existing work has focused on fractional anisotropy (FA) and mean diffusivity (MD) measures that are thought to capture demyelination and axonal degradation and relate to cognitive decline in normal aging and AD. However, these measures are susceptible to partial volume effects. Here, we evaluated whether executive function and memory are associated with FA and MD after deploying a free‐water (FW) elimination post‐processing method that separates fluid (FW) from tissue (FW‐corrected FA and MD).MethodWe examined 489 non‐demented men in the Vietnam Era Twin Study of Aging (VETSA) at mean age 68. Executive function was based on 6 tasks spanning inhibition, shifting, and working memory. Memory was based on 7 subtests from the Logical Memory, Visual Reproductions, and California Verbal Learning tests. Analyses focused on 11 cortical white matter tracts across three metrics: FW, FW‐corrected FA, and FW‐corrected MD. Analyses controlled for age, scanner, diabetes, hypertension, race, and ethnicity. We used false discovery rate to account for multiple testing.ResultBetter executive functioning was associated with lower FW across all 11 tracts. Better memory was associated with lower FW in 3 tracts: the superior longitudinal fasciculus (SLF) and two sections of the inferior frontal gyrus (opercularis and triangularis). Despite widespread differences with FW, there was only one significant association with intracellular metrics (executive function and FW‐corrected FA in the SLF). Finally, indicators of cognitive reserve (education or general cognitive ability assessed in early adulthood) did not moderate these associations between cognition and white matter microstructure.ConclusionOur findings leveraged a post‐processing method that separates extracellular fluid (FW) from intracellular tissue (FA, MD). We found that cognitive abilities in early old age are associated primarily with extracellular white matter microstructure (FW), which demonstrated global associations with executive function. Finally, there was no evidence that indicators of cognitive reserve influenced the strength of the association between cognition and white matter, at least in this sample of non‐demented men.

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