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Abstract Background White matter hyperintensities (WMH) are considered hallmark features of cerebral small vessel disease and have recently been linked to Alzheimer’s disease (AD) pathology. Their distinct spatial distributions, namely periventricular versus deep WMH, may differ by underlying age-related and pathobiological processes contributing to cognitive decline. We aimed to identify the spatial patterns of WMH using the 4-scale Fazekas visual assessment and explore their differential association with age, vascular health, AD imaging markers, namely amyloid and tau burden, and cognition. Because our study consisted of scans from GE and Siemens scanners with different resolutions, we also investigated inter-scanner reproducibility and combinability of WMH measurements on imaging. Methods We identified 1144 participants from the Mayo Clinic Study of Aging consisting of a population-based sample from Olmsted County, Minnesota with available structural magnetic resonance imaging (MRI), amyloid, and tau positron emission tomography (PET). WMH distribution patterns were assessed on FLAIR-MRI, both 2D axial and 3D, using Fazekas ratings of periventricular and deep WMH severity. We compared the association of periventricular and deep WMH scales with vascular risk factors, amyloid-PET, and tau-PET standardized uptake value ratio, automated WMH volume, and cognition using Pearson partial correlation after adjusting for age. We also evaluated vendor compatibility and reproducibility of the Fazekas scales using intraclass correlations (ICC). Results Periventricular and deep WMH measurements showed similar correlations with age, cardiometabolic conditions score (vascular risk), and cognition, (p

Abstract Dementia with Lewy bodies (DLB) is a neurodegenerative condition often co-occurring with Alzheimer’s disease (AD) pathology. Characterizing white matter tissue microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) may help elucidate the biological underpinnings of white matter injury in individuals with DLB. In this study, diffusion tensor imaging (DTI) and NODDI metrics were compared in 45 patients within the dementia with Lewy bodies spectrum (mild cognitive impairment with Lewy bodies (n = 13) and probable dementia with Lewy bodies (n = 32)) against 45 matched controls using conditional logistic models. We evaluated the associations of tau and amyloid-β with DTI and NODDI parameters and examined the correlations of AD-related white matter injury with Clinical Dementia Rating (CDR). Structural equation models (SEM) explored relationships among age, APOE ε4, amyloid-β, tau, and white matter injury. The DLB spectrum group exhibited widespread white matter abnormalities, including reduced fractional anisotropy, increased mean diffusivity, and decreased neurite density index. Tau was significantly associated with limbic and temporal white matter injury, which was, in turn, associated with worse CDR. SEM revealed that amyloid-β exerted indirect effects on white matter injury through tau. We observed widespread disruptions in white matter tracts in DLB that were not attributed to AD pathologies, likely due to α-synuclein-related injury. However, a fraction of the white matter injury could be attributed to AD pathology. Our findings underscore the impact of AD pathology on white matter integrity in DLB and highlight the utility of NODDI in elucidating the biological basis of white matter injury in DLB.

Abstract INTRODUCTION Age‐related and Alzheimer's disease (AD) dementia–related neurodegeneration impact brain health. While morphometric measures from T1‐weighted scans are established biomarkers, they may be less sensitive to earlier changes. Neurite orientation dispersion and density imaging (NODDI), offering biologically meaningful interpretation of tissue microstructure, may be an advanced brain health biomarker. METHODS We contrasted regional gray matter NODDI and morphometric evaluations concerning their correlation with (1) age, (2) clinical diagnosis stage, and (3) tau pathology as assessed by AV1451 positron emission tomography. RESULTS Our study hypothesizes that NODDI measures are more sensitive to aging and early AD changes than morphometric measures. One NODDI output, free water fraction (FWF), showed higher sensitivity to age‐related changes, generally better effect sizes in separating mild cognitively impaired from cognitively unimpaired participants, and stronger associations with regional tau deposition than morphometric measures. DISCUSSION These findings underscore NODDI's utility in capturing early neurodegenerative changes and enhancing our understanding of aging and AD. Highlights Neurite orientation dispersion and density imaging can serve as an effective brain health biomarker for aging and early Alzheimer's disease (AD). Free water fraction has higher sensitivity to normal brain aging. Free water fraction has stronger associations with early AD and regional tau deposition.

The clinical usefulness MRI biomarkers for aging and dementia studies relies on precise brain morphological measurements; however, scanner and/or protocol variations may introduce noise or bias. One approach to address this is post-acquisition scan harmonization. In this work, we evaluate deep learning (neural style transfer, CycleGAN and CGAN), histogram matching, and statistical (ComBat and LongComBat) methods. Participants who had been scanned on both GE and Siemens scanners (cross-sectional participants, known as Crossover (n = 113), and longitudinally scanned participants on both scanners (n = 454)) were used. The goal was to match GE MPRAGE (T1-weighted) scans to Siemens improved resolution MPRAGE scans. Harmonization was performed on raw native and preprocessed (resampled, affine transformed to template space) scans. Cortical thicknesses were measured using FreeSurfer (v.7.1.1). Distributions were checked using Kolmogorov-Smirnov tests. Intra-class correlation (ICC) was used to assess the degree of agreement in the Crossover datasets and annualized percent change in cortical thickness was calculated to evaluate the Longitudinal datasets. Prior to harmonization, the least agreement was found at the frontal pole (ICC = 0.72) for the raw native scans, and at caudal anterior cingulate (0.76) and frontal pole (0.54) for the preprocessed scans. Harmonization with NST, CycleGAN, and HM improved the ICCs of the preprocessed scans at the caudal anterior cingulate (>0.81) and frontal poles (>0.67). In the Longitudinal raw native scans, over- and under-estimations of cortical thickness were observed due to the changing of the scanners. ComBat matched the cortical thickness distributions throughout but was not able to increase the ICCs or remove the effects of scanner changeover in the Longitudinal datasets. CycleGAN and NST performed slightly better to address the cortical thickness variations between scanner change. However, none of the methods succeeded in harmonizing the Longitudinal dataset. CGAN was the worst performer for both datasets. In conclusion, the performance of the methods was overall similar and region dependent. Future research is needed to improve the existing approaches since none of them outperformed each other in terms of harmonizing the datasets at all ROIs. The findings of this study establish framework for future research into the scan harmonization problem.

Abstract Multi-compartment modelling of white matter microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) can provide information on white matter health through neurite density index and free water measures. We hypothesized that cerebrovascular disease, Alzheimer’s disease, and TDP-43 proteinopathy would be associated with distinct NODDI readouts of white matter damage which would be informative for identifying the substrate for cognitive impairment. We identified two independent cohorts with multi-shell diffusion MRI, amyloid and tau PET, and cognitive assessments: specifically, a population-based cohort of 347 elderly randomly sampled from the Olmsted county, Minnesota, population and a clinical research-based cohort of 61 amyloid positive Alzheimer’s dementia participants. We observed an increase in free water and decrease in neurite density using NODDI measures in the genu of the corpus callosum associated with vascular risk factors, which we refer to as the vascular white matter component. Tau PET signal reflective of 3R/4R tau deposition was associated with worsening neurite density index in the temporal white matter where we measured parahippocampal cingulum and inferior temporal white matter bundles. Worsening temporal white matter neurite density was associated with (antemortem confirmed) FDG TDP-43 signature. Post-mortem neuropathologic data on a small subset of this sample lend support to our findings. In the community-dwelling cohort where vascular disease was more prevalent, the NODDI vascular white matter component explained variability in global cognition (partial R2 of free water and neurite density = 8.3%) and MMSE performance (8.2%) which was comparable to amyloid PET (7.4% for global cognition and 6.6% for memory). In the AD dementia cohort, tau deposition was the greatest contributor to cognitive performance (9.6%), but there was also a non-trivial contribution of the temporal white matter component (8.5%) to cognitive performance. The differences observed between the two cohorts were reflective of their distinct clinical composition. White matter microstructural damage assessed using advanced diffusion models may add significant value for distinguishing the underlying substrate (whether cerebrovascular disease versus neurodegenerative disease caused by tau deposition or TDP-43 pathology) for cognitive impairment in older adults. Graphical abstract

Context: Cerebral blood flow (CBF) measurement using arterial spin labelling (ASL) MRI sequences has recently emerged as a prominent tool in dementia research. Aims: To establish association between quantified regional cerebral perfusion and gray matter (GM) volumes with cognitive measures in mild cognitive impairment (MCI) and early Alzheimer's Dementia (AD), using three dimensional fast spin echo pseudo-continuous ASL MRI sequences. Settings and Design: Hospital-based cross-sectional study. Methods and Material: Three age-matched groups, i.e., 21 cognitively normal healthy controls (HC), 20 MCI and 19 early AD patients diagnosed using neuropsychological tests and who consented for multimodality 3T MRI were recruited for the study. Statistical Analysis Used: Statistical parametric mapping and regions of interest (ROI) multivariate analysis of variance was used to ascertain differences between patients and controls on MRI-volumetry and ASL. Linear regression was used to assess relationship between CBF with GM atrophy and neuropsychological test measures. Results: Compared to HC, patients with MCI and AD had significantly lower quantified perfusion in posterior cingulate and lingual gyri, over hippocampus in MCI, with no differences noted between MCI and AD. Atrophy over the middle temporal gyrus and hippocampus differentiated AD from MCI. No significant positive correlations were noted between perfusion and GM volumes in ROI with the exception of temporal neocortex. Significantly positive coefficient b-value (p < 0.01) were apparent between global cognition with CBF in precuneus, temporal neocortex and precuneus volume, with negative b-values noted between medial temporal CBF for global cognition and recall scores. Conclusions: ROI-based CBF measurements differentiated MCI and AD from HC; volumetry of medial and neocortical temporal GM separates AD from MCI. Correlations between CBF and neuropsychology are variable and require further longitudinal studies to gauge its predictive utility on cognitive trajectory in MCI.

Our goal was to understand the complex relationship between age, sex, midlife risk factors, and early white matter changes measured by diffusion tensor imaging (DTI) and their role in the evolution of longitudinal white matter hyperintensities (WMH). We identified 1564 participants (1396 cognitively unimpaired, 151 mild cognitive impairment and 17 dementia participants) with age ranges of 30–90 years from the population-based sample of Mayo Clinic Study of Aging. We used computational causal structure discovery and regression analyses to evaluate the predictors of WMH and DTI, and to ascertain the mediating effect of DTI on WMH. We further derived causal graphs to understand the complex interrelationships between midlife protective factors, vascular risk factors, diffusion changes, and WMH. Older age, female sex, and hypertension were associated with higher baseline and progression of WMH as well as DTI measures (P ≤ 0.003). The effects of hypertension and sex on WMH were partially mediated by microstructural changes measured on DTI. Higher midlife physical activity was predictive of lower WMH through a direct impact on better white matter tract integrity as well as an indirect effect through reducing the risk of hypertension by lowering BMI. This study identified key risks factors, early brain changes, and pathways that may lead to the evolution of WMH.

Brain infarctions are closely associated with future risk of stroke and dementia. Our goal was to report (i) frequency and characteristics that differentiate symptomatic vs. silent brain infarctions (SBI) on MRI and (ii) frequency and location by vascular distribution (location of stroke by major vascular territories) in a population based sample. From Mayo Clinic Study of Aging, 347 participants (≥50 years) with infarcts detected on their first MRI were included. Infarct information was identified visually on a FLAIR MRI image and a vascular territory atlas was registered to the FLAIR image data in order to identify the arterial territory of infarction. We identified the subset with a clinical history of stroke based on medical chart review and used a logistic regression to evaluate the risk factors associated with greater probability of a symptomatic stroke vs. SBI. We found that 14% of all individuals with infarctions had a history of symptomatic stroke (Silent: n = 300, symptomatic: n = 47). Factors associated with a symptomatic vs. SBI were size which had an odds ratio of 3.07 (p < 0.001), greater frequency of hypertension (odds ratio of 4.12, p = 0.025) and alcohol history (odds ratio of 4.58, p = 0.012). The frequency of infarcts was greater in right hemisphere compared to the left for SBI. This was primarily driven by middle cerebral artery (MCA) infarcts (right = 60%, left = 40%, p = 0.005). While left hemisphere strokes are more common for symptomatic carotid disease and in clinical trials, right hemispheric infarcts may be more frequent in the SBI group.

Abstract Introduction The aim of this study was to examine white matter hyperintensities (WMH) and fractional anisotropy (FA) in empirically derived incident mild cognitive impairment (MCI) subtypes. Methods We evaluated 188 participants with incident MCI in the Mayo Clinic Study of Aging (MCSA) identified as having one of four cluster‐derived subtypes: subtle cognitive impairment, amnestic, dysnomic, and dysexecutive. We used linear regression models to evaluate whole brain and regional WMH volumes. We examined fractional anisotropy (FA) on a subset of 63 participants with diffusion tensor imaging. Results Amnestic and dysexecutive subtypes had higher WMH volumes in differing patterns than cognitively unimpaired; the dysexecutive subtype had higher WMH than subtle cognitive impairment. There was widespread WM degeneration in long association and commissural fibers in the amnestic, dysnomic, and dysexecutive subtypes, and corpus callosum FA accounted for significant variability in global cognition. Discussion White matter changes likely contribute to cognitive symptoms in incident MCI.