Faculty Bibliography

PURPOSE/UNASSIGNED:To investigate the short-T1 fraction as a potential biomarker of white matter myelin integrity, using myelin histology as ground truth. METHODS/UNASSIGNED:short-T1 fraction data were acquired from two elderly volunteers with WMHs to demonstrate translational feasibility. RESULTS/UNASSIGNED:significant reductions in short-T1 fractions were detected within WMHs. CONCLUSION/UNASSIGNED:The short-T1 fraction correlated with myelin content in postmortem brain white matter, supporting its potential as a clinically translatable biomarker of myelin integrity.

Aging is the primary risk factor for synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), and independently contributes to motor dysfunction. This review summarizes motor system degeneration in aging and disease, focusing on the primary motor cortex (M1), its white matter tracts, and the nigrostriatal system. In healthy aging, M1 exhibits cortical thinning, myelin loss, reduced perfusion, and iron deposition. The motor cortex-derived corticospinal and corticostriatal pathways undergo microstructural decline, often linked to vascular factors. The substantia nigra (SN) demonstrates selective neuronal loss, oxidative stress, iron deposition, and synaptic reduction, contributing to motor impairment. In synucleinopathies, these age-related vulnerabilities are exacerbated by disease-specific pathology. In PD, progressive dopaminergic neuron loss in the SN is a core feature, detectable with advanced magnetic resonance imaging (MRI) markers of iron, neuromelanin, and microstructure. PD pathophysiology extends beyond the nigrostriatal system, involving M1 dysfunction and widespread white matter abnormalities linked to motor deficits and cognitive impairment. DLB is characterized by widespread involvement of cortex (especially posterior), limbic, basal ganglia, brainstem, and cholinergic system, accounting for its early cognitive impairment, neuropsychiatric, motor, and autonomic symptoms. In contrast, MSA is characterized by oligodendroglial α-synuclein inclusions, causing multi-system degeneration, with characteristic atrophy and microstructural disruption in the putamen, pons, and cerebellum that aid differential diagnosis. Multiparametric MRI offers in vivo insights into structural, microstructural, hemodynamic, metabolic, and pathological changes underlying motor dysfunction in aging and neurodegenerative disorders. Understanding the convergence of age-related motor neuron degeneration and disease-specific pathology is essential for elucidating disease mechanisms, identifying early biomarkers, and developing targeted therapies in synucleinopathies.

BACKGROUND:Motor performance declines with aging, yet how somatotopic subregions of the primary motor cortex (M1) and corticospinal tract (CST) show region-specific structural and functional changes during aging remains unclear. METHODS:We analyzed T1- and T2-weighted MRI, multi-delay arterial spin labeling, and multi-shell diffusion data from 339 right-handed adults in the Human Connectome Project-Aging database. Measures included M1 cerebral blood flow (CBF), arterial transit time (ATT), intracortical myelin (T1/T2 ratio), and CST integrity. M1 was divided into face, upper-limb, and lower-limb subregions using mrGrad, and corresponding CST subdivisions were reconstructed. RESULTS:Across age groups, CBF was highest in upper-limb M1 and lowest in lower-limb M1, while myelin content was highest in lower-limb regions of both M1 and CST. Aging was associated with prolonged ATT, reduced CBF, and altered T1/T2 ratio across all subregions, whereas the upper-limb CST showed relatively preserved microstructure. These imaging features of M1 and CST were linked to somatic motor performance. CONCLUSION/CONCLUSIONS:M1 and CST exhibit distinct somatotopic gradients in structure and function. Aging affects motor homunculus subregions and their pathways in region-specific ways. Multiparametric MRI has potential to characterize early motor decline and provides insights into neural mechanisms underlying somatotopic motor functions in older adults.

Conventional imaging techniques lack the resolution and sensitivity to adequately characterize cerebral small-vessel abnormalities (CSVA) in vivo. This study aimed to overcome these limitations and evaluate the feasibility of a novel MRI technique called Microvascular In-vivo Contrast Revealed Origins (MICRO), which uses an ultrasmall superparamagnetic iron oxide (USPIO) contrast agent (Ferumoxytol) to resolve the cerebral microvascular architecture with a level of anatomical and physiological detail not previously achievable in vivo. Fifty-nine Parkinson's disease (PD) patients underwent MICRO MRI based on susceptibility-weighted imaging (SWI). Three independent raters identified and categorized CSVAs as large developmental venous anomalies (DVAs), micro DVAs, engorged vessels, and diminished vessels. The location of each CSVAs was documented, and its association with white matter hyperintensities (WMHs) was assessed. The MICRO imaging protocol demonstrated excellent inter-rater agreement for identifying these CSVAs. Our findings show a high prevalence of CSVAs in PD patients, with engorged vessels being the most common type (49.06% of subjects). Both engorged vessels (72.41%) and micro DVAs (81.82%) were highly associated with WMHs. CSVAs were most frequently observed in the periventricular white matter (n=28), deep white matter (n=32), and putamen (n=14), suggesting regional distribution pattern of detectable CSVAs. This work establishes MICRO as a feasible, reliable platform for in vivo microvascular mapping with potential applications in neurovascular research.

OBJECTIVE:ratio (TPR) imaging approach and evaluates its ability to characterize MS lesions alongside other quantitative MRI (qMRI) metrics. METHODS:and PD values were used to illustrate TPR contrast. Statistical analyses included Wilcoxon rank-sum tests and Spearman correlations (p < 0.05). RESULTS:* (92 ms) values but lower MTR (37.3%) and MTsat (1.57%) compared to hypointense lesions (1085 ms; 0.88 a.u.; 64 ms; 46%; 2.48%, respectively). QSM values varied across lesion types. INTERPRETATION/CONCLUSIONS:, PD, and MT metrics, consistent with demyelination. In contrast, hypointense lesions may reflect tissue changes associated with repair processes such as remyelination.

BACKGROUND/UNASSIGNED:The deep gray matter nuclei (DGMN)-including the thalamus, caudate, putamen, and pallidum-are essential for cognitive, motor, and affective functions and are highly susceptible to age-related degeneration. However, the combined effects of aging and sex on DGMN volume, microstructure, and perfusion remain incompletely characterized. METHODS/UNASSIGNED:Using data from 652 healthy adults (36-89 years) from the Human Connectome Project-Aging cohort, we examined volumetric and perfusion changes across the DGMN. High-resolution T1- and T2-weighted MRI and multi-delay pseudo-continuous arterial spin labeling (pCASL) were used to quantify normalized volume, T1/T2 ratio, cerebral blood flow (CBF), and arterial transit time (ATT) in DGMN regions after perivascular spaces were removed. Age-related trajectories were modeled using linear and quadratic regression, and differences between sexes were examined, with false discovery rate correction applied. RESULTS/UNASSIGNED:Advancing age was associated with significant volumetric decline in all DGMN regions (p < 0.001), prolonged ATT, and reduced CBF, particularly in the caudate and thalamus. The T1/T2 ratio exhibited region-specific nonlinear trajectories, peaking in mid-adulthood and declining thereafter, reflecting its underlying age-related processes of demyelination and iron accumulation. Sex-stratified analyses suggested modest differences in T1/T2, ATT, and CBF trajectories; however, no significant age × sex interactions were observed after correction for multiple comparisons. DGMN volumes correlated negatively with ATT, while T1/T2 ratio correlated inversely with CBF, indicating more complex interactions between structure, tissue properties, and perfusion. CONCLUSIONS/UNASSIGNED:This large-scale quantitative MRI study delineates distinct age-related trajectories of DGMN over adult lifespan. Integrating volumetric, T1/T2 ratio, and multi-delay ASL metrics-while correcting for perivascular spaces-enhances sensitivity to subtle changes and provides normative benchmarks for detecting early neurodegenerative alterations.

Ceramide transporter syndrome (CerTra syndrome) is a rare neurodevelopmental disorder caused by pathogenic variants in CERT1 gene encoding ceramide transporter (CERT). These variants disrupt ceramide transport and sphingolipid homeostasis, leading to a clinical phenotype that includes developmental delay, movement abnormalities, and structural brain anomalies. Despite growing recognition of this condition, detailed neuroimaging and neuropathological characterization remain limited. Here, we present a 12-year-old girl with a pathogenic CERT1 variant complicated by sudden unexplained death, who presented with unreported neuroimaging abnormalities in choroid plexus (ChP) and perivascular space (PVS). Clinical Magnetic Resonance Imaging (MRI) obtained approximately 10 years prior to death, as well as postmortem MRI, revealed bilateral cystic enlargement of the ChP and prominent PVS filled with abundant proteinaceous material in white matter. Neuropathological examination demonstrated marked ChP epithelial disorganization, reduced aquaporin-1 (AQP1) expression, cyst formation, and focal calcifications, which may be associated with disturbances in cerebrospinal fluid (CSF) dynamics. These findings raise the possibility that CERT1 variants may be associated with ChP architectural changes and altered perivascular clearance.

Aging is an important risk factor for Parkinson's disease (PD). Characterizing age-related alterations in the nigrostriatal system may help identify early vulnerability prior to overt neurodegeneration. We aimed to delineate aging trajectories of structure and hemodynamics of the nigrostriatal system and examine their associations with motor and cognitive functions. We analyzed 486 healthy adults from Human Connectome Project-Aging dataset, stratified into younger (≤ 60 years) and older (> 60 years) groups. Motor, cognitive, and motor cognition functions were assessed. Multiparametric MRI included T1- and T2-weighted, multi-delay arterial spin labeling, and multi-shell diffusion imaging. Volumes, T1/T2 ratio, arterial transit time (ATT), and cerebral blood flow (CBF) were quantified in the nigrostriatal nuclei. The nigrostriatal tract (NST) was reconstructed and segmented along the nigra-to-striatum axis. Diffusion metrics and quantitative anisotropy were derived. A composite nigrostriatal aging index (NAI) was generated using principal component analysis. Older adults exhibited reduced substantia nigra and putamen volumes, increased caudate volume, prolonged ATT, and reduced CBF across nigrostriatal nuclei. The NST showed segment-specific age trajectories, with increased diffusivity after age 60. Imaging alterations in nigrostriatal nuclei and tract segments correlated with declines in motor, cognitive, and motor-cognitive performance. The NAI increased more steeply after age 60 and predicted poorer behavioral performance exclusively in older adults. Healthy aging is characterized by coordinated structural and hemodynamic alterations within the nigrostriatal system associated with functional decline. The composite NAI provides a sensitive framework for detecting early nigrostriatal vulnerability in older adults prior to overt neurodegeneration.

The choroid plexus (ChP), a highly vascularized epithelial organ within the brain ventricles, sustains cerebrospinal fluid (CSF) production, regulates the blood-CSF barrier (BCSFB), and coordinates neuroimmune responses. Beyond these classical roles, the ChP is increasingly recognized as an active interface within brain clearance pathways, facilitating CSF-interstitial fluid (ISF) exchange and contributing to metabolic waste removal. Structural and functional disruption of the ChP/BCSFB accompanies aging and has been linked to the pathogenesis of neurodegenerative disorders. Magnetic resonance imaging (MRI) provides a powerful, non-invasive platform for in vivo characterization of the ChP. This review summarizes recent advances in MRI techniques tailored to ChP imaging, including quantitative assessments of microstructure, perfusion, permeability, and dynamic water exchange, and highlights their applications in aging and dementia. Converging evidence suggests that MRI-derived indices of ChP integrity are associated with cognitive status and may facilitate early detection and longitudinal monitoring of disease trajectories, particularly in Alzheimer's disease and related dementias (AD/ADRD). Continued development and application of advanced MRI approaches will be essential for further elucidating the role of the ChP in neurodegeneration and for evaluating its potential clinical utility.

INTRODUCTION/BACKGROUND:Though brain fog is common in Long-coronavirus disease 2019 (Long-COVID), the incidence of mild cognitive impairment (MCI) is unknown. METHODS:In an observational cohort study, recovered COVID-positive, Long-COVID, and COVID-negative subjects underwent blinded evaluation using National Alzheimer's Coordinating Center (NACC) and National Institute on Aging (NIA) -Alzheimer's Association diagnostic criteria for dementia and MCI. The cumulative incidence of MCI was calculated for each group, and the hazard of MCI was compared between groups. RESULTS:Among 260 subjects, the cumulative incidence of MCI over 4.4 years was higher with Long-COVID (27%) versus recovered-COVID (5%) or COVID-negative status (1%). There was a higher hazard of MCI for patients with Long-COVID compared to those without (hazard ratio [HR] 3.93, 95% confidence interval [CI] 1.86-8.31, p < 0.001), and specifically for the Alzheimer's disease (AD) -related MCI subtype (HR 3.20, 95% confidence interval [CI] 1.14-9.00, p = 0.027). DISCUSSION/CONCLUSIONS:The cumulative incidence and adjusted hazard of MCI (and specifically AD-related MCI) at 4.4 years was significantly higher among Long-COVID patients compared to recovered-COVID and COVID-negative controls.