Faculty Bibliography

BACKGROUND AND PURPOSE/OBJECTIVE:Although visibility of Deep Medullary Veins (DMVs) has been suggested as an imaging biomarker for cerebral small vessel disease (CSVD) and brain atrophy, qualitative visual assessment of DMVs may lack reliability. In this study, we used a rigorous, automated approach to segment DMVs on SWI and to estimate a vein voxel fraction (VVF). We hypothesized that VVF would be associated with vascular risk factors, imaging markers of CSVD, and brain volumes. MATERIAL AND METHODS/METHODS:A retrospective analysis of data from participants enrolled in studies of brain aging and prediction of Alzheimer's disease. All underwent 3T MRI (T1WI, FLAIR, SWI, and arterial spin labeling), clinical evaluations, and laboratory tests to assess vascular risks. A SWI image processing pipeline included denoising, bias field correction, adaptive histogram equalization, and multi-scale Jerman filtering that yielded vesselness maps. The vein voxel fraction (VVF) was calculated as a ratio of DMVs voxels in a periventricular region to the volume of the periventricular region. White matter hyperintensities, microbleeds, brain volumes, and CBF were also assessed. RESULTS:This study included 131 cognitively healthy participants, 71 (65, 76) years (median, Q1, Q3), (51%) female, and a subgroup of subjects with cognitive impairment (n=30, 69 (59, 76) years, 43% female). In the unimpaired group, the VVF positively correlated with systolic blood pressure and body mass index. It showed an inverse association with lateral ventricle volume (all at p < 0.05). It was related to white matter hyperintensities volume only in unadjusted analysis. CONCLUSION/CONCLUSIONS:Vein voxel fraction was associated with increased weight and high blood pressure. Possibly, these observations reflect venous stasis. These factors should be accounted for while evaluating brain venous system with SWI. In addition, subcortical atrophy was related to less visible DMVs.

BackgroundPeople with subjective cognitive decline (SCD) are at increased risk of Alzheimer's disease. Prior research has suggested that amygdala volume may be more sensitive than hippocampal volume in detecting differences between SCD and age-matched controls, as well as in predicting SCD conversion to mild cognitive impairment. However, the microstructure underlying this volumetric change remains unclear.ObjectiveThis study evaluated amygdala microstructural differences in SCD versus control participants as well as associations between amygdala microstructure and volume, age, memory performance, anxiety, and depression using diffusion imaging.MethodsDiffusion tensor imaging, diffusion kurtosis imaging, and neurite orientation dispersion and density imaging were fit to diffusion MRI images. Group differences and correlations between diffusion metrics, age, memory, anxiety, and depression were assessed in 123 SCD versus 194 age-matched controls over age 55.ResultsIn the left amygdala, SCD participants had significantly lower fractional anisotropy (FA), lower kurtosis fractional anisotropy (KFA), and higher free water fraction (FWF). KFA was lower in the right amygdala in SCD. There were no significant group differences in the amygdala volume. Bilateral KFA negatively correlated with FWF, a marker of neuroinflammation and neurodegeneration. Left FA negatively correlated with orientation dispersion index, a marker of neuritic branching. Right KFA correlated with age only in SCD, while left FA correlated with anxiety only in controls.ConclusionsKFA is sensitive to group differences between SCD and controls in bilateral amygdala. KFA may reflect neuroinflammation and increased sensitivity to aging in the amygdala in SCD.

INTRODUCTION/BACKGROUND:Measuring plasma biomarkers effectively assesses early-stage Alzheimer's disease. METHODS:Subjects were categorized as cognitively unimpaired (CU) (n = 66), CU with subjective cognitive decline (SCD) (n = 100), and mild cognitive impairment (MCI) (n = 25). Plasma biomarkers measured were amyloid beta (Aβ) 40, Aβ42, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181 (pTau181), neuroinflammatory biomarkers, and blood-brain barrier biomarkers. Amyloid and tau positron emission tomography (PET) imaging was performed in 186 and 144 subjects, respectively. RESULTS:Comparing those having MCI, both CU and SCD participants had significantly lower amyloid PET standardized uptake value ratio (SUVR) (p < 0.001; p = 0.005). Higher amyloid PET SUVR was significantly associated with higher pTau181 (p = 0.001) and a higher pTau181/Aβ42 ratio (p < 0.001). Higher tau PET SUVR was associated with lower plasma Aβ42 (p = 0.020), older age (p = 0.005), higher GFAP (p = 0.020), and lower interleukin-8 levels (p < 0.001). DISCUSSION/CONCLUSIONS:Our study supports plasma biomarker monitoring of at-risk patients at various stages of pre-dementia.

Reliable structural brain measurements are essential for studying neurodegeneration and for designing adequately powered aging and Alzheimer's disease (AD) research. We evaluated the test-retest reliability of FreeSurfer 7.1 morphometric measures in 100 older adults (mean age 73.5 years) ranging from cognitively unimpaired to dementia. Each participant underwent two T1-weighted 3T MRI scans on the same scanner within a short interval (mean 5.5 weeks), minimizing biological change. Segmentation was performed in both standard cross-sectional and longitudinal FreeSurfer modes, focusing on AD-relevant volumes of entorhinal cortex, hippocampus, lateral ventricles, choroid plexus, and the AD cortical thickness signature. Reliability was quantified using absolute and root-mean-square test-retest differences, standard deviation of differences, and intraclass correlation coefficients. Longitudinal processing improved precision by 15-50% across most measures compared with cross-sectional processing, with the largest gain observed for entorhinal thickness. Larger, anatomically well-defined regions (e.g., hippocampus, AD signature) demonstrated higher reliability than small structures or those with complex geometry (e.g., entorhinal cortex, choroid plexus). Image quality, indexed by the Euler characteristic, was the only factor significantly associated with measurement variability; reliability was unrelated to age, sex, cognitive status, inter-scan interval, or amyloid/tau PET burden. Power analyses indicated that detecting a 1% within-individual change requires sample sizes ranging from 36 (AD signature) to >300 (entorhinal cortex). We observed low reliability of choroid plexus volumetry by FreeSurfer 7. These results provide practical benchmarks for expected FreeSurfer measurement variability in older adults. They highlight the advantages of longitudinal processing and rigorous quality control for research on brain aging and AD.

BACKGROUND:Identifying early neuropathological changes in Alzheimer's disease (AD) is important for improving treatment efficacy. Among quantitative MRI measures, transverse relaxation time (T2) has been shown to reflect tissue microstructure relevant in aging and neurodegeneration; however, findings regarding T2 changes in both normal aging and AD have been inconsistent. The association between T2 and amyloid-beta (Aβ) accumulation, a hallmark of AD pathology, is also unclear, particularly in cognitively normal individuals who may be in preclinical stages of the disease. PURPOSE/OBJECTIVE:To investigate longitudinal hippocampal T2 changes in a cognitively normal cohort of older adults and their association with global Aβ accumulation. STUDY TYPE/METHODS:Retrospective, longitudinal. SUBJECTS/METHODS:56 cognitively normal adults between 55 and 90 years of age (17 males and 39 females). FIELD STRENGTH/SEQUENCE/UNASSIGNED:3 Tesla; multi-echo spin echo sequence for T2 mapping; 18F-florbetaben positron emission tomography for Aβ measurement. ASSESSMENT/RESULTS:Bilateral hippocampal T2 and volume were extracted to relate to Aβ PET measurements. To understand variations in AD risk, participants were separated into Aβ-high and Aβ-low subgroups using a predetermined threshold. STATISTICAL TESTS/METHODS:Linear mixed-effect models and general linear models were used. A p-value < 0.025 was considered significant to account for bilateral comparisons. RESULTS:Older age was associated with increased T2 in the bilateral hippocampus (left: β = 0.30, right: β = 0.25) and smaller hippocampal volume on the left (β = -0.12). In the Aβ-low subgroup, both longitudinal T2 increase rates (β = 0.65) in the left hippocampus and bilateral cross-sectional T2 (left: β = 0.64, right: β = 0.46) were positively correlated with Aβ PET, independent of hippocampal volume. DATA CONCLUSION/CONCLUSIONS:This study provided in vivo evidence linking hippocampal T2 to Aβ accumulation in cognitively normal aging individuals, suggesting that quantitative T2 may be sensitive to microstructural changes accompanying early Aβ pathology, such as neuroinflammation, demyelination, and reduced tissue integrity. EVIDENCE LEVEL/METHODS:3. TECHNICAL EFFICACY/UNASSIGNED:Stage 2.

BACKGROUND:. However, the microstructural alterations driving these differences are unclear. Here, we assess associations of MK and KFA with neurite orientation dispersion and density imaging (NODDI) and magnetization transfer imaging (MTI) metrics, which provide a more specific characterization of tissue microstructure. METHOD/METHODS:(75 SCD) ages 55-88 were included in the analysis. Participants were defined as SCD if they endorsed problems with their memory and in the control group otherwise. Diffusion images were processed to obtain MK, Radial Kurtosis (RK), Axial Kurtosis (AK) and KFA from DKI and Neurite Density (ND) and Orientation Dispersion (OD), a marker of neurite organization, from NODDI. MTI was used to calculate the Magnetization Transfer Ratio (MTR), a marker of myelin and potentially amyloid aggregation. Mean metric values were calculated for bilateral amygdala (Figure 1). Between-group comparisons were conducted using Wilcoxon rank-sum tests, corrected for multiple testing. Associations between DKI, NODDI, and MTR metrics were examined using linear models corrected for age and sex. RESULT/RESULTS:SCD had lower KFA, higher MK, and higher RK in the right amygdala (Table 1). KFA had a weak negative correlation with ND, while MK and RK had strong positive correlations (Figure 2A-C). Only MK had a weak positive correlation with OD (Figure 2D-F). Neither KFA, MK, nor RK correlated with MTR (Figure 2G-I). CONCLUSION/CONCLUSIONS:DKI metrics are more sensitive to amygdala changes in SCD than NODDI metrics or MTR. Lower KFA, higher MK, and higher RK were associated with higher ND but not MTR, suggestive of dendritic or glial branching. Higher MK was additionally associated with higher OD, potentially indicating reduced neurite organization. Further analyses on the impact of these amygdala changes on SCD related neuropsychiatric symptoms are needed. References 1. Flaherty R, Sui YV, Li M, et al. Alzheimers Dement. 2024;20(S9):e093982. 2. Shafto MA, Tyler LK, Dixon M, et al. BMC Neurol. 2014;14(1):1-25.

BACKGROUND:Deep medullary veins (DMVs) play important roles within the cerebrovascular network related to brain drainage and clearance. Although they have been previously correlated with brain volume, it is unknown whether their count is specifically correlated with subcortical or cortical volume changes. PURPOSE/OBJECTIVE:This study aims to better understand the relationship between DMVs, subcortical (lateral ventricle to intracranial volume ratio (ICV)) and cortical atrophy (cortical thickness) to identify whether DMVs can be a predictor of volume changes in these regions. METHODS:We performed a retrospective analysis of 332 cognitively healthy subjects previously followed between 2010 and 2019. Imaging and patient charts were analyzed for baseline demographic and clinical characteristics. Patients underwent a standardized cognitive interview and received a magnetic resonance imaging scan to assess DMVs, cortical thickness, lateral ventricle and global gray matter (GM) volumes, white matter lesions (WMLs) and microbleeds. RESULTS:Among 332 patients (62% female, median age 70), lateral ventricle/ICV was significantly related to DMV count (p<0.001). Similarly, sex stratified analyses confirmed that a larger lateral ventricle/ICV ratio, but not cortical thickness or global GM volumes, was associated with fewer DMVs. In the entire group, subcortical atrophy remained a significant predictor of DMVs even after accounting for baseline characteristics, WMLs, microbleeds and total gray matter volume. CONCLUSIONS:In a large cohort of cognitively unaffected people, subcortical, but not cortical, atrophy was significantly correlated with venous health as measured by DMVs. Reduced DMVs are a strong predictor of ventricular enlargement.

Purpose To evaluate intravoxel incoherent motion (IVIM) biomarkers across different MRI vendors and software programs for breast cancer characterization in a two-site study. Materials and Methods This institutional review board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study included 106 patients (with 18 benign and 88 malignant lesions) who underwent bilateral diffusion-weighted imaging (DWI) between February 2009 and March 2013. DWI was performed using 1.5-T (n = 6) or 3-T MRI scanners from two vendors using single-shot spin-echo echo-planar imaging or twice-refocused, bipolar gradient single-shot turbo spin-echo readout with multiple b values between 0 and 1000 sec/mm². IVIM parameters tissue diffusivity (D_t