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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: Most older adults live with multiple chronic disease conditions, yet the effect of multiple diseases on brain function remains unclear.Methods: We examine the relationship between disease multimorbidity and brain activity using regional cerebral blood flow (rCBF) 15O-water PET scans from 97 cognitively normal participants (mean baseline age 76.5) in the Baltimore Longitudinal Study of Aging (BLSA). Multimorbidity index scores, generated from the presence of 13 health conditions, were correlated with PET data at baseline and in longitudinal change (n = 74) over 5.05 (2.74 SD) years.Results: At baseline, voxel-based analysis showed that higher multimorbidity scores were associated with lower relative activity in orbitofrontal, superior frontal, temporal pole and parahippocampal regions, and greater activity in lateral temporal, occipital, and cerebellar regions. Examination of the individual health conditions comprising the index score showed hypertension and chronic kidney disease individually contributed to the overall multimorbidity pattern of altered activity. Longitudinally, both increases and decreases in activity were seen in relation to increasing multimorbidity over time. These associations were identified in orbitofrontal, lateral temporal, brainstem, and cerebellar areas.Conclusion: Together, these results show that greater multimorbidity is associated with widespread areas of altered brain activity, supporting a link between health and changes in aging brain function. [ABSTRACT FROM AUTHOR]