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Background: While diffusion MRI derived free‐water (FW) metrics have shown promise in predicting cognitive impairment and decline in aging and Alzheimer's disease (AD), it is unclear whether hippocampal FW metrics would be superior to traditional structural neuroimaging biomarkers (i.e., hippocampal volume, AD Schwarz Signature, AD McEvoy Signature). We examined the relationships between hippocampal FW metrics and traditional neuroimaging biomarkers with longitudinal memory and executive function. Method: Vanderbilt Memory & Aging Project participants [n = 298, age at baseline: 73 ± 7 years, 40% mild cognitive impairment (MCI)] underwent longitudinal neuropsychological assessment and brain MRI over a 7 year follow‐up (mean: 3 ± 2 years) period. Structural MRI was used to quantify hippocampal volume in addition to Schwarz and McEvoy signatures. Diffusion MRI in conjunction with the FW elimination technique was used to quantify hippocampal FW and FW‐corrected fractional anisotropy (FAFWcorr). Linear regression was used to determine the association of each biomarker with baseline memory and executive function. A subsequent competitive model analysis was conducted to determine how much additional variance was provided by each biomarker compared to the covariate only model, which included age, sex, race/ethnicity, apolipoprotein‐e4 status, cognitive status, and modified Framingham Stroke Risk Profile scores. Additionally, linear mixed‐effects regression was used to determine the association between baseline biomarker values with longitudinal memory and executive function scores. All analyses were corrected for multiple comparisons using the FDR procedure. Result: At baseline, all biomarkers (excluding hippocampal FAFWcorr) were significantly associated with cognitive performance (Table 1), with hippocampal FW exhibiting the most significant association for memory (pFDR = 3.92×10−6) and executive function (pFDR = 5.35×10−3). Competitive models revealed that hippocampal FW contributed the most unique variance beyond covariates for memory (ΔRadj2 = 3.87%) and executive function (ΔRadj2 = 1.59%). Longitudinal models (Table 2, Figure 1) largely mirrored cross‐sectional models by demonstrating that hippocampal FW was most significantly associated with longitudinal decline in memory (pFDR = 5.04×10−13) and executive function (pFDR = 6.15×10−5). Conclusion: This study shows that hippocampal FW is a sensitive biomarker for cognitive impairment and decline, and provides strong evidence for further exploration of this measure in aging and AD. [ABSTRACT FROM AUTHOR]

Background: Although several prior diffusion MRI studies have indicated a role of medial temporal lobe (MTL) white matter microstructural decline in Alzheimer's disease (AD), it is unclear which AD risk genes are associated with this decline. The goal of this study is to leverage multi‐site harmonized diffusion MRI data to investigate the relationship between 73 AD risk variants and microstructural decline in MTL tracts. Method: The dataset used in this study was collated from three 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 1,308 participants (70% cognitively unimpaired, 27% MCI, 3% AD) aged 50+ who had both diffusion MRI and genotype data and includes a total of 3,442 imaging sessions (mean number of visits: 2.68 ± 1.66, interval range: 1 ‐ 12 years). Genotype data was preprocessed using a standardized approach, and the dosage of the 73 AD risk variants was extracted. Diffusion MRI data was preprocessed using the PreQual pipeline and free‐water (FW) correction was conducted to obtain FW and FW‐corrected fractional anisotropy (FAFWcorr) maps. FW and FAFWcorr were quantified within 5 MTL tracts, including the cingulum, fornix, uncinate fasciculus, inferior longitudinal fasciculus, which were subsequently harmonized using the Longitudinal ComBat package. Linear regression was conducted to investigate the association between AD risk variants and MTL microstructure at baseline, while linear mixed effects regression was used for longitudinal analysis. All models were corrected for age at baseline and sex and corrected for multiple comparisons using the FDR approach. Result: At baseline, APOE‐ε4 dosage was strongly associated with MTL FW in all tracts, with additional associations for TMEM106B and CR1 dosages with fornix FW (Table 1). Longitudinally, APOE‐ε4 dosage was a strong predictor of MTL FW decline in all tracts, and KAT8, CR1, and TMEM106B dosages exhibited significant associations with fornix microstructural decline (Table 2 and Figure 1). Conclusion: This study suggests that although APOE‐ε4 is the strongest predictor of white matter microstructural decline, several other AD risk genes (i.e., CR1, SPI1, TMEM106B, KAT8) contribute to decline, particularly in the fornix. [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: Cerebrospinal fluid (CSF) platelet‐derived growth factor receptor‐β (PDGFR‐β) is an emerging biomarker hypothesized to reflect pericyte damage. CSF PDGFR‐β levels are increased in Alzheimer's disease (AD), but it is unknown if pericyte injury contributes to cerebrovascular changes common in AD. We examined if PDGFR‐β relates to changes in cerebral blood flow (CBF) and white matter injury in older adults. Method: Vanderbilt Memory and Aging Project participants (n = 152, baseline age 73±7 years, 43% mild cognitive impairment [MCI]) underwent baseline lumbar puncture and serial brain MRI over a 7‐year (5.5±2.3) follow‐up period. CSF PDGFR‐β concentrated was measured by immunoassay. MRI included pseudo‐continuous arterial spin‐labeling to quantify CBF, T2‐FLAIR to quantify white matter hyperintensities (WMHs), and diffusion tensor imaging (DTI) to quantify white matter microstructural integrity. Ordinary least squares regression and linear mixed‐effects models related baseline CSF PDGFR‐β to baseline and longitudinal whole brain and regional CBF, WMH, and DTI metrics, adjusting for baseline demographic variables, modified Framingham Stroke Risk Profile, cognitive status, apolipoprotein‐ε4 status, and regional tissue volume. Longitudinal models adjusted for follow‐up time. Follow‐up models tested a CSF PDGFR‐β x cognitive status interaction. Result: In main models, higher CSF PDGFR‐β levels were cross‐sectionally associated with lower mean diffusivity (indicating better microstructural integrity) in white matter tracts in the frontal, temporal, parietal, and occipital lobes (p‐values<0.03) but were unrelated to WMHs (p‐values>0.18). Models investigating associations with longitudinal white matter variables were null (p‐values>0.35). CSF PDGFR‐β cross‐sectionally interacted with diagnosis on temporal lobe CBF, such that higher CSF PDGFR‐β related to higher CBF in MCI participants (p = 0.01). In longitudinal models, baseline CSF PDGFR‐β interacted with cognitive status on whole brain and occipital lobe CBF (p‐values<0.04). Stratified models showed higher baseline CSF PDGFR‐β related slower reductions in longitudinal CBF in whole brain (p = 0.02), frontal (p = 0.04), temporal (p = 0.02), parietal (p = 0.01), and occipital lobes (p = 0.008) in cognitively unimpaired participants only. Conclusion: Among older adults, higher CSF PDGFR‐β levels are associated with better white matter integrity at study entry and predict slower reductions in longitudinal CBF among cognitively unimpaired individuals. Results suggest that higher PDGFR‐β levels may reflect subclinical vascular remodeling that provides protection to future cerebrovascular compromise. [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]

Background: Cortical 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). Method: We 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. Result: Better 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. Conclusion: Our 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) neurofilament light (NFL) is a biomarker of neuroaxonal injury associated with cognitive decline, neurodegeneration, and white matter damage. Recent advances allow for plasma measurement of NFL, increasing accessibility of this biomarker. However, it is unknown if CSF and plasma NFL have similar prognostic value for predicting white matter damage. This study relates baseline CSF and plasma NFL concentrations to longitudinal change in white matter integrity in older adults. Method: Vanderbilt Memory & Aging Project participants free of dementia at baseline (n=147, 72±6 years, 32% female) underwent baseline fasting lumbar puncture for CSF sampling and venous blood draw for plasma sampling. Participants completed serial 3T diffusion tensor imaging to assess white matter microstructural integrity at baseline, 18‐months, 3‐years, and 5‐years (follow‐up 4.3±1.3 years). Voxel‐wise linear mixed effects models with follow‐up time interaction terms related baseline CSF and plasma NFL separately to white matter microstructural trajectory, adjusting for baseline demographic and health variables, apolipoprotein E‐ε4 status, diagnosis, and follow‐up time. Follow‐up models tested interactions with diagnosis, amyloid‐β (Aβ), and phosphorylated tau (p‐tau). Result: CSF and plasma NFL were correlated (r=0.50, p<0.001). In the entire sample, CSF NFL related to faster white matter microstructural integrity decline in frontal, parietal, occipital, and subcortical regions (corrected p‐values<0.05). Plasma NFL related to faster white matter microstructural integrity decline in frontal and subcortical regions (corrected p‐values<0.05). CSF (largest β=5.7x10‐9) and plasma (largest β=3.1x10‐7) associations were similar in strength. CSF NFL interacted with diagnosis and Aβ (corrected p‐values<0.04), with associations driven by MCI and Aβ negative participants. Plasma NFL interacted with Aβ and p‐tau (corrected p‐values<0.04), with associations driven by Aβ and p‐tau negative participants. Conclusion: Among older adults, increased baseline CSF and plasma NFL concentrations predicted faster longitudinal decline in white matter integrity. While CSF NFL may relate to more widespread future white matter damage compared to plasma, plasma NFL could be an accessible biomarker for assessing future risk of white matter damage, particularly in individuals without Aβ or p‐tau pathology. CSF NFL may be a better prognostic biomarker in individuals with MCI, whereas plasma NFL has similar prognostic ability across diagnostic groups. [ABSTRACT FROM AUTHOR]

Background: Subjective cognitive decline (SCD) is a perceived cognitive change prior to objective cognitive deficits, and although it is associated with Alzheimer's disease (AD) pathology, it likely results from multiple underlying pathologies. We investigated the association of white matter microstructure to SCD as a sensitive and early marker of cognitive decline and quantified the contribution of white matter microstructure separate from amyloidosis. Method: Vanderbilt Memory & Aging Project participants with diffusion MRI data and a 45‐item measure of SCD were included (n=237, 73±7 years, 37% female). A subset of participants (n=104) underwent a fasting lumbar puncture for quantification of amyloid‐β (CSF Aβ42). Diffusion MRI data was post‐processed using the free‐water (FW) elimination technique, which allowed quantification of extracellular (FW) and intracellular compartment (fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) microstructure. Microstructural values were quantified within 11 cognitive‐related white matter tracts, including medial temporal lobe, frontal transcallosal, and fronto‐parietal tracts. General linear modeling related each tract to SCD adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile scores, APOE‐ε4 carrier status, diagnosis, Geriatric Depression Scale scores, and total white matter volume. Competitive model analyses were conducted to determine if white matter microstructural values have a unique role in SCD separate from CSF Aβ42. Result: FW‐corrected radial diffusivity (RDT) was related to SCD in 6 tracts: cingulum bundle (β=3.52x106; p=0.001), inferior longitudinal fasciculus (β=2.77x106; p=0.005), as well as inferior frontal gyrus (IFG) pars opercularis (β=1.98x106; p=0.008), IFG pars triangularis (β=2.69x106; p=0.008), medial frontal gyrus (β=2.46x106; p=0.007), and middle frontal gyrus (β=2.47x106; p=0.014) transcallosal tracts. While CSF Aβ42 was related to SCD in our cohort (β=‐0.021; p=0.020), competitive model analyses revealed that fornix and IFG pars triangularis transcallosal tract RDT contributed unique variance to SCD beyond CSF Aβ42. Conclusion: Medial temporal lobe and frontal transcallosal tract microstructure is an important driver of SCD independent of early AD pathology. Given RDT appears to be the most significant predictor of SCD, demyelination may be an early contributor to cognitive decline. These results highlight the value of incorporating multiple biomarkers to help disentangle the mechanistic heterogeneity of SCD as an early stage of cognitive decline. [ABSTRACT FROM AUTHOR]