Faculty Bibliography

While hippocampal atrophy in Alzheimer's disease is well-documented, research on microstructural integrity of hippocampal pathways to selected cortical regions in healthy aging populations remains limited. Four hundred seventy-five healthy individuals aged 36-90 from the Human Connectome Project Aging (HCP-A) dataset were analyzed. Hippocampal fiber pathways, including the "Papez," "Prefrontal," "Occipital," and "Parietal" pathways, were extracted from whole-brain tractography and characterized by fractional anisotropy (FA) and mean diffusivity (MD), neurite density index (NDI), and orientation distribution index (ODI). Partial linear and quadratic nonlinear correlation analyses were conducted to examine the relationship between age, cognition, and diffusion metrics, adjusted by hippocampus volumes. While FA, MD, and ODI demonstrated linear age-related changes, NDI exhibited a quadratic pattern. MD was identified as the most age-sensitive parameter. Among all pathways, the "Prefrontal" pathway showed the most pronounced microstructural changes in both males and females, characterized by reduced FA and NDI and increased MD and ODI with age (FA: r = -0.31 to -0.40; NDI: r² = 0.30-0.31; MD/ODI: r = 0.23-0.48; p < 0.01). Similar changes were observed in the "Occipital" pathway (FA: r = -0.28 to -0.39; MD/ODI: r = 0.32-0.50; p < 0.01), with NDI reduction present only in females (r² = 0.18, p < 0.01). In the "Parietal" pathway, changes were detected only in females, with lower FA (r = -0.29, p < 0.01) and higher ODI (r = 0.24, p < 0.01). Additionally, age-related cognitive decline was significantly associated with microstructural changes in the "Occipital" (FA: r = 0.29; MD: r = -0.28; ODI: r = -0.25; p < 0.001) and "Prefrontal" pathways (FA: r = 0.27; MD: r = -0.25; NDI: r = 0.25; ODI: r = -0.22; p < 0.01) in females. This study revealed age- and cognition-related changes in hippocampal pathways across the adult lifespan. These findings provide normative references for hippocampal-cortical connectivity changes associated with healthy aging and its potential relevance to Alzheimer's disease and related dementias.

BACKGROUND:Motor and cognitive decline are hallmark features of aging. In the primary motor cortex (M1), pyramidal neurons project to the corticospinal tract (CST), a well-established motor pathway, and send collaterals to the ipsilateral striatum, forming the corticostriatal tract (CStrT). While the CST has been extensively studied, the role of the CStrT in motor and cognitive aging remains poorly understood. METHODS:We analyzed T1- and T2-weighted MRI, multi-delay arterial spin labeling, and multi-shell diffusion MRI data from 339 right-handed healthy adults (aged 36-90 years) in the Human Connectome Project-Aging dataset. Age-related trajectories of M1 structure and hemodynamics, as well as CST and CStrT microstructure, were assessed. Segment-wise along-tract analyses were conducted to identify localized tract degeneration. Mediation analyses were performed to examine whether tract integrity linked M1 atrophy to motor and cognitive performance. RESULTS:With age, M1 exhibited reduced volume and hemodynamics, altered T1/T2 ratio, and increased cortical curvature, reflecting structural and hemodynamic alterations. Along-tract analyses revealed localized microstructural degeneration in the CST adjacent to M1, whereas the CStrT showed more extensive degeneration along its trajectory. These tract changes were associated with structural and hemodynamic alterations in M1. Furthermore, integrity of the dominant (left) CST and CStrT mediated the relationship between ipsilateral M1 atrophy and motor decline. Notably, CStrT integrity also mediated the association between M1 atrophy and motor cognition decline. CONCLUSION/CONCLUSIONS:These findings establish age-related structural and functional degeneration of M1 and its pathways, highlighting the CStrT as a critical mediator between motor cortical atrophy and both motor and cognitive decline. These normative imaging markers of healthy aging may help inform the early detection of neurodegenerative diseases.

The choroid plexus (ChP) is critical to the glymphatic system of the human brain through its primary function as the source of cerebrospinal fluid (CSF) production, which plays an important role in brain waste clearance. Developing noninvasive imaging techniques to assess ChP is crucial for studying its function and age-related neurofluid dynamics. In this study, we developed a relaxation-selective intravoxel incoherent motion (IVIM) technique to assess tissue and fluid compartments in the ChP of 83 middle-aged to elderly participants (age: 61.5 ± 17.1 years) and 15 young controls (age: 30.7 ± 2.9 years). Using a 3-T MRI scanner, we implemented T1- and T2-selective IVIM approaches, including Fluid-Attenuated Inversion Recovery IVIM (FLAIR-IVIM), LongTE-IVIM, and Vascular Space Occupancy-LongTE-IVIM (VASO-LongTE-IVIM), to measure diffusivity and volume fractions of fluid compartments in ChP. Our results showed that FLAIR-IVIM identified an additional interstitial fluid (ISF) compartment with free-water-like diffusivity in ChP. We then evaluated the aging effects on microvascular perfusion and ISF in ChP. Compared to younger adults, older adults exhibited increased ChP volume, reduced perfusion, decreased ISF volume fraction, and lower tissue diffusivity. Relaxation-selective IVIM may offer enhanced specificity for characterizing age-related changes in ChP structure and fluid dynamics.

Sodium magnetic resonance imaging (MRI) is highly sensitive to cellular ionic balance due to tenfold difference in sodium concentration across membranes, actively maintained by the sodium-potassium (Na⁺-K⁺) pump. Disruptions in this pump or membrane integrity, as seen in neurological disorders like epilepsy, multiple sclerosis, bipolar disease, and mild traumatic brain injury, lead to increased intracellular sodium. However, this cellular-level alteration is often masked by the dominant extracellular sodium signal, making it challenging to distinguish sodium populations with mono- vs. bi-exponential transverse (T₂) decays-especially given the low signal-to-noise ratio (SNR) even at an advanced clinical field of 3 Tesla. Here, we propose a novel technique that leverages intrinsic difference in T₂ decays by acquiring single-quantum images at multiple echo times (TEs) and applying voxel-wise matrix inversion for accurate signal separation. Using numerical models, agar phantoms, and human subjects, we achieved high separation accuracy in phantoms (95.8% for mono-T₂ and 72.5-80.4% for bi-T₂) and demonstrated clinical feasibility in humans. This approach may enable early detection of neurological disorders and early assessment of treatment responses at the cellular level using sodium MRI at 3 T.

Sex differences in hippocampal aging have been increasingly recognized, with females showing greater vulnerability to neurodegeneration, particularly after menopause. However, the underlying neurobiological mechanisms remain unclear, especially at the level of hippocampal subfields. Leveraging high-resolution T1-, T2-weighted, and multi-delay arterial spin labeling MRI from 650 adults in the Human Connectome Project-Aging dataset, we examined sex-specific alterations in hippocampal subfield volume, arterial transit time (ATT), and cerebral blood flow (CBF) across the adult lifespan. All hippocampal subfields showed age-related atrophy and ATT prolongation. An age × sex interaction effect on ATT was observed in CA1 and CA2, indicating that age-related increases in ATT were more pronounced in females than in males in these subfields. Moreover, females exhibited more pronounced hippocampal subfields CBF reductions with aging and atrophy, while males showed relatively preserved CBF, with an increase in subiculum perfusion. Furthermore, CA1 showed the lowest perfusion and the strongest association with atrophy among hippocampal subfields. To investigate the potential impact of menopausal hormonal changes on sex-specific patterns, we explored the hypothalamic structure and hemodynamic alterations during aging and their effects on the hippocampus, given that hypothalamus regulates gonadal hormone secretion through the hypothalamic-pituitary-gonadal axis. We found significant hypothalamic atrophy during aging in both sexes, accompanied by ATT prolongation exclusively in females, which was associated with hippocampal atrophy and impaired hemodynamics. Our study highlights the intricate interplay between hippocampal structure and vascular function, revealing sex- and subfield-specific aging trajectories. These findings provide a normative quantitative imaging reference to age-related neurodegenerative diseases such as Alzheimer's Disease.

The intricate neurofluid dynamics and balance is essential in preserving the structural and functional integrity of the brain. Key among these forces are: hemodynamics, such as heartbeat-driven arterial and venous blood flow, and hydrodynamics, such as cerebrospinal fluid (CSF) circulation. The delicate interplay between these dynamics is crucial for maintaining optimal homeostasis within the brain. Currently, the widely accepted framework for understanding brain functions is the Monro-Kellie's doctrine, which posits a constant sum of intracranial CSF, blood flow and brain tissue volumes. However, in recent decades, there has been a growing interest in exploring the dynamic interplay between these elements and the impact of external factors, such as daily changes in body position. CSF circulation in particular plays a crucial role in the context of neurodegeneration and dementia, since its dysfunction has been associated with impaired clearance mechanisms and accumulation of toxic substances. Despite the implementation of various invasive and non-invasive imaging techniques to investigate the intracranial hemodynamic or hydrodynamic properties, a comprehensive understanding of how all these elements interact and are influenced by body position remains wanted. Establishing a comprehensive overview of this topic is therefore crucial and could pave the way for alternative care approaches. In this review, we aim to summarize the existing understanding of intracranial hemodynamic and hydrodynamic properties, fundamental for brain homeostasis, along with factors known to influence their equilibrium. Special attention will be devoted to elucidating the effects of body position shifts, given their significance and remaining ambiguities. Furthermore, we will explore recent advancements in imaging techniques utilized for real time and non-invasive measurements of dynamic body fluid properties in-vivo.

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.

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.

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.

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.