Faculty Bibliography

BACKGROUND:The choroid plexus (ChP), a highly vascularized structure within the ventricles, is essential for cerebrospinal fluid (CSF) production and metabolic waste clearance, crucial for neurofluid homeostasis and cognitive function. ChP enlargement is seen in normal aging and neurodegenerative diseases like Alzheimer's disease (AD). Despite its key role of in the blood-CSF barrier (BCSFB), detailed studies on age-related changes in its perfusion and microstructure remain limited. METHODS:We analyzed data from 641 healthy individuals aged between 36 and 90, using the Human Connectome Project Aging (HCP-A) dataset. Volumetric, perfusion, and diffusion metrics of the ChP were derived from structural MRI, arterial spin labeling (ASL), and diffusion-weighted imaging (DWI), respectively. Partial correlations were used to explore age-related ChP changes, and independent t-tests to examine sex differences across age decades. One-way ANOVA was employed to compare perfusion characteristics among ChP, gray matter (GM), and white matter (WM). Relationships between volume, perfusion, and diffusion were investigated, adjusting for age and sex. Additionally, the distribution of cyst-like structures within the ChP and their diffusion/perfusion MRI characteristics were analyzed across different age groups. RESULTS: = 0.16, P < 0.001). Perfusion characteristics showed significant differences between the ChP, GM, and WM (P < 0.001). Both the ChP and GM exhibited age-related declines in CBF, with a more pronounced decline in the ChP. A negative correlation was observed between the age-related increase in ChP volume and the decrease in CBF, suggesting compensatory dystrophic hyperplasia in response to perfusion decline. Cyst-like structures in ChP, characterized by lower MD and reduced CBF, were found to be more prevalent in older individuals. CONCLUSIONS:Our findings provide a detailed quantitative assessment of age-related changes in ChP perfusion and diffusion, which may affect CSF production and circulation, potentially leading to waste solute accumulation and cognitive impairment. GRANT SUPPORT/UNASSIGNED:This work was supported in part by the NIH U01AG052564, P30AG066512, P01AG060882, RF1 NS110041, R01 NS108491, U24 NS135568.

BACKGROUND:The choroid plexus (ChP), a densely vascularized structure, has drawn increasing attention for its involvement in brain homeostasis and waste clearance. While the volumetric changes have been explored in many imaging studies, few studies have investigated the vascular degeneration associated with aging in the ChP. PURPOSE/OBJECTIVE:To investigate the sub-structural characteristics of the ChP, particularly the vascular compartment using high-resolution 7T imaging enhanced with Ferumoxytol, an ultrasmall super-paramagnetic iron oxide, which greatly increase the susceptibility contrast for vessels. STUDY TYPE/METHODS:Prospective. SUBJECTS/METHODS:Forty-nine subjects without neurological disorders (age: 21-80 years; 42 ± 17 years; 20 females). FIELD STRENGTH/SEQUENCE/UNASSIGNED:7-T with 2D and 3D T2* GRE, 3D MPRAGE T1, 2D TSE T2, and 2D FLAIR. ASSESSMENT/RESULTS:ratio) and susceptibility change (Δχ) induced by Ferumoxytol were analyzed on 3D GRE-derived susceptibility-weighted imaging and quantitative susceptibility mapping, respectively. STATISTICAL TESTS/METHODS:Independent t-test, Mann-Whitney U test, and Chi-square test were utilized for group comparisons. The relationship between age and ChP's vascular alterations was examined using Pearson's correlation. Intra-class coefficient was calculated for inter-observer agreement. A P value <0.05 was considered statistically significant. RESULTS:2D GRE images demonstrated superior contrast and accurate delineation of ChP substructures (ICC = 0.86). Older subjects exhibited a significantly smaller vascular density (16.5 ± 4.34%) and lower Δχ (22.10 ± 12.82 ppb) compared to younger subjects (24.85 ± 6.84% and 34.64 ± 12.69 ppb). Vascular density and mean Δχ within the ChP negatively correlated with age (r = -0.48, and r = -0.45). DATA CONCLUSION/CONCLUSIONS:Ferumoxytol-enhanced 7T images can demonstrate ChP alterations in elderly with decreased vascular density and expansion of nonvascular compartment. EVIDENCE LEVEL/METHODS:1 TECHNICAL EFFICACY: Stage 2.

Vascular pathologies are among the most common contributors to neurodegenerative changes across the spectrum of normal aging to dementia. Cerebral small vessel disease (SVD) encompasses a wide range of conditions affecting capillaries, small arteries, and arterioles, as well as perivascular spaces and fluid dynamics in the brain, playing a significant role in vascular contributions to cognitive impairment and dementia (VCID). These factors can accelerate the progression of SVD and neuronal degeneration. Since aging is the primary risk factor for Alzheimer's disease (AD) and AD-related dementias (ADRD), this Research Topic aims to gather recent research to better understand vascular contributions to healthy aging and age-related cognitive impairment. Other risk factors include diabetes, lifestyle factors, high cholesterol, vascular inflammation, and immune remodeling, all of which can accelerate cognitive dysfunction progression. This special issue includes a total of 21 articles comprising Reviews, Perspectives, and Original Research articles. The articles cover various technical and biological aspects related to recent progress in aging and dementia research. We aim to promote research exchange across different fields, including imaging, VCID, molecular biology, neuroinflammation, and immunology. Most papers in this special issue focus on understanding the disease mechanisms of AD/ADRD and developing new therapeutic strategies.

Histopathological studies suggest that cerebral small vessel tortuosity is crucial in age-related blood flow reduction and cellular degeneration. However, in vivo evidence is lacking. Here, we used Ferumoxytol-enhanced 7T MRI to directly visualize cerebral small vessels (>300 µm), enabling the identification of vascular tortuosity and exploration of its links to age, tissue atrophy, and vascular risk factors. High-resolution 2D/3D gradient echo MRI at 7T enhanced with Ferumoxytol, an ultrasmall superparamagnetic iron oxide (USPIO), was obtained and analyzed for cerebral small medullary artery tortuosity from 37 healthy participants (21-70 years; mean/SD: 38±14 years; 19 females). Tortuous artery count and tortuosity indices were compared between young and old groups. Age effects on vascular tortuosity were examined through partial correlations and multiple linear regression, adjusting for sex, body mass index (BMI), blood pressure (BP), and other vascular risk factors. Associations between tortuous medullary arteries and tissue atrophy, perivascular spaces (PVS), and white matter (WM) hyperintensities were explored. Age and BMI, rather than BP, showed positive correlations with both tortuous artery count and tortuosity indices. A significant correlation existed between the number of tortuous arteries and WM atrophy. WM lesions were found in proximity to or at the distal ends of tortuous medullary arteries, especially within the deep WM. Moreover, the elderly population displayed a higher prevalence of PVS, including those containing enclosed tortuous arteries. Leveraging the blooming effect of Ferumoxytol, 7T MRI excels in directly detecting cerebral small arterial tortuosity in vivo, unveiling its associations with age, BMI, tissue atrophy, WMH and PVS.

Reduced cerebral blood flow (CBF) in the temporoparietal region and gray matter volumes (GMVs) in the temporal lobe were previously reported in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, the temporal relationship between reductions in CBF and GMVs requires further investigation. This study sought to determine if reduced CBF is associated with reduced GMVs, or vice versa. Data came from 148 volunteers of the Cardiovascular Health Study Cognition Study (CHS-CS), including 58 normal controls (NC), 50 MCI, and 40 AD who had perfusion and structural MRIs during 2002-2003 (Time 2). Sixty-three of the 148 volunteers had follow-up perfusion and structural MRIs (Time 3). Forty out of the 63 volunteers received prior structural MRIs during 1997-1999 (Time 1). The relationships between GMVs and subsequent CBF changes, and between CBF and subsequent GMV changes were investigated. At Time 2, we observed smaller GMVs (p<0.05) in the temporal pole region in AD compared to NC and MCI. We also found associations between: (1) temporal pole GMVs at Time 2 and subsequent declines in CBF in this region (p=0.0014) and in the temporoparietal region (p=0.0032); (2) hippocampal GMVs at Time 2 and subsequent declines in CBF in the temporoparietal region (p=0.012); and (3) temporal pole CBF at Time 2 and subsequent changes in GMV in this region (p = 0.011). Therefore, hypoperfusion in the temporal pole may be an early event driving its atrophy. Perfusion declines in the temporoparietal and temporal pole follow atrophy in this temporal pole region.

PURPOSE/OBJECTIVE:Abnormalities in cerebral veins are a common finding in many neurological diseases, yet there is a scarcity of MRI techniques to assess venous hemodynamic function. The present study aims to develop a noncontrast technique to measure a novel blood flow circulatory measure, venous transit time (VTT), which denotes the time it takes for water to travel from capillary to major veins. METHODS:relaxation time. The validity of the measured VTT was tested by studying the VTT along the anatomically known flow trajectory of venous vessels as well as using a physiological vasoconstrictive challenge of caffeine ingestion. Finally, we compared the VTT measured with VICTR MRI to a bolus-tracking method using gadolinium-based contrast agent. RESULTS:VTT was measured to be 3116.3 ± 326.0 ms in the posterior superior sagittal sinus (SSS), which was significantly longer than 2865.0 ± 390.8 ms at the anterior superior sagittal sinus (p = 0.004). The test-retest assessment showed an interclass correlation coefficient of 0.964. VTT was significantly increased by 513.8 ± 239.3 ms after caffeine ingestion (p < 0.001). VTT measured with VICTR MRI revealed a strong correlation (R = 0.84, p = 0.002) with that measured with the contrast-based approach. VTT was found inversely correlated to cerebral blood flow and venous oxygenation across individuals. CONCLUSION/CONCLUSIONS:A noncontrast MRI technique, VICTR MRI, was developed to measure the VTT of the brain.

Studying the relationship between cerebral oxygen utilization and cognitive impairment is essential to understanding neuronal functional changes in the disease progression of multiple sclerosis (MS). This study explores the potential of using venous susceptibility in internal cerebral veins (ICVs) as an imaging biomarker for cognitive impairment in relapsing-remitting MS (RRMS) patients. Quantitative susceptibility mapping derived from fully flow-compensated MRI phase data was employed to directly measure venous blood oxygen saturation levels (S_vO₂) in the ICVs. Results revealed a significant reduction in the susceptibility of ICVs (212.4 ± 30.8 ppb vs 239.4 ± 25.9 ppb) and a significant increase of S_vO₂ (74.5 ± 1.89% vs 72.4 ± 2.23%) in patients with RRMS compared with age- and sex-matched healthy controls. Both the susceptibility of ICVs (r = 0.508, p = 0.031) and the S_vO₂ (r = -0.498, p = 0.036) exhibited a moderate correlation with cognitive decline in these patients assessed by the Paced Auditory Serial Addition Test, while no significant correlation was observed with clinical disability measured by the Expanded Disability Status Scale. The findings suggest that venous susceptibility in ICVs has the potential to serve as a specific indicator of oxygen metabolism and cognitive function in RRMS. .

Mapping the small venous vasculature of the hippocampus in vivo is crucial for understanding how functional changes of hippocampus evolve with age. Oxygen utilization in the hippocampus could serve as a sensitive biomarker for early degenerative changes, surpassing hippocampal tissue atrophy as the main source of information regarding tissue degeneration. Using an ultrahigh field (7T) susceptibility-weighted imaging (SWI) sequence, it is possible to capture oxygen-level dependent contrast of submillimeter-sized vessels. Moreover, the quantitative susceptibility mapping (QSM) results derived from SWI data allow for the simultaneous estimation of venous oxygenation levels, thereby enhancing the understanding of hippocampal function. In this study, we proposed two potential imaging markers in a cohort of 19 healthy volunteers aged between 20 and 74 years. These markers were: 1) hippocampal venous density on SWI images and 2) venous susceptibility (Δχ_vein) in the hippocampus-associated draining veins (the inferior ventricular veins (IVV) and the basal veins of Rosenthal (BVR) using QSM images). They were chosen specifically to help characterize the oxygen utilization of the human hippocampus and medial temporal lobe (MTL). As part of the analysis, we demonstrated the feasibility of measuring hippocampal venous density and Δχ_vein in the IVV and BVR at 7T with high spatial resolution (0.25 × 0.25 × 1 mm³). Our results demonstrated the in vivo reconstruction of the hippocampal venous system, providing initial evidence regarding the presence of the venous arch structure within the hippocampus. Furthermore, we evaluated the age effect of the two quantitative estimates and observed a significant increase in Δχ_vein for the IVV with age (p = 0.006, r² = 0.369). This may suggest the potential application of Δχ_vein in IVV as a marker for assessing changes in atrophy-related hippocampal oxygen utilization in normal aging and neurodegenerative diseases such as AD and dementia.

PURPOSE/OBJECTIVE:has important applications in cerebrovascular diseases. At present, these sequences are performed separately. This study aims to develop a novel MRI technique to simultaneously estimate these parameters. METHODS:* mapping). Test-retest repeatability and initial clinical application in two patients with stroke were evaluated. RESULTS:estimation was highly reliable, with voxelwise coefficient of variation (CoV) <5%. The CoV for arterial transit time and cerebral blood flow was 16% ± 3% and 25% ± 9%, respectively. The results from the two patients with stroke demonstrated that parametric maps derived from the proposed method can detect both ischemic and hemorrhagic stroke. CONCLUSION/CONCLUSIONS:The proposed method is a promising technique for multi-parametric mapping and has potential use in patients with stroke.

INTRODUCTION/UNASSIGNED:Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique with simultaneous (during stimulation) and cumulative effects (after repeated sessions) on blood flow and neuronal metabolism. These effects remain mostly unclear especially in multiple sclerosis (MS). This work aims to elucidate brain metabolic and hemodynamic underpinnings of tDCS and its potential therapeutic impact in MS patients using quantitative tDCS-MRI. METHODS/UNASSIGNED:) were obtained at pre-tDCS, during-tDCS and post-tDCS. RESULTS/UNASSIGNED:and CBF in pre-tDCS follow up, reaching the magnitudes measured at baseline during-tDCS. DISCUSSION/UNASSIGNED:TDCS induces an acute surge in metabolic activity persisting immediately after the stimulation is removed. Moreover, treatment composed of repeated tDCS-aCT paired sessions contributes to establishing long-lasting increases in neuronal activity.