Increased periventricular thalamic damage gradient in multiple sclerosis detected by quantitative gradient echo MRI
(2024) Multiple Sclerosis and Related Disorders, 90, art. no. 105834, .
Samara, A.a , Xiang, B.a , Judge, B.b , Ciotti, J.R.c , Yablonskiy, D.A.b , Cross, A.H.a , Brier, M.R.a b
a Department of Neurology, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, United States
c Department of Neurology, University of South Florida, Tampa, FL, United States
Abstract
Objective: Thalamic tissue damage in multiple sclerosis (MS) follows a ‘surface-in’ gradient from the ventricular surface. The clinical consequences of this gradient are not completely understood. Using quantitative gradient-recalled echo (qGRE) MRI, we evaluated a periventricular thalamic gradient of tissue integrity in MS and its relationship with clinical variables. Methods: Structural and qGRE MRI scans were acquired for a cohort of MS patients and healthy controls (HC). qGRE-derived R2t* values were used as a measure of tissue integrity. Thalamic segmentations were divided into 1-mm concentric bands radiating from the ventricular surface, excluding the CSF-adjacent band. Median R2t* values within these bands were used to calculate the periventricular thalamic gradient. Results: We included 44 MS patients and 17 HC. R2t* increased slightly with distance from the ventricular surface in HC. MS patients had a steeper periventricular thalamic gradient compared to HC (mean slope 0.55 vs. 0.36; p < 0.001), which correlated with longer disease duration (β = 0.001 /year; p = 0.027) and higher Expanded Disability Status Scale (EDSS) score (β = 0.07 /EDSS point; p = 0.019). Left and right thalamus were symmetrically affected. Conclusions: We detected an increased thalamic gradient in MS in vivo using qGRE MRI, which correlated with disease duration and greater clinical disability. These findings further support the ‘surface-in’ pathology hypothesis in MS and suggest a CSF-mediated process given symmetric bi-thalamic involvement. © 2024 The Author(s)
Author Keywords
MRI; Multiple sclerosis; Quantitative gradient-recalled echo (qGRE); Thalamus
Document Type: Article
Publication Stage: Final
Source: Scopus
Effect of Human Head Shape on the Risk of Traumatic Brain Injury: A Gaussian Process Regression-Based Machine Learning Approach
(2024) Military Medicine, 189 (Supplement_3), pp. 608-617.
Upadhyay, K.a , Jagani, R.b , Giovanis, D.G.c , Alshareef, A.d , Knutsen, A.K.e , Johnson, C.L.f , Carass, A.g , Bayly, P.V.h , Shields, M.D.c , Ramesh, K.T.b
a Department of Mechanical and Industrial Engineering, Louisiana State University, Baton Rouge, LA 70803, United States
b Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD 21218, United States
c Department of Civil and Systems Engineering, Johns Hopkins University, Baltimore, MD 21218, United States
d Department of Mechanical Engineering, University of South Carolina, Columbia, SC 29208, United States
e Center for Neuroscience and Regenerative Medicine, Henry M. Jackson Foundation, Bethesda, MD 20817, United States
f Department of Biomedical Engineering, University of Delaware, Newark, DE 19713, United States
g Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, MD 21218, United States
h Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, United States
Abstract
Introduction: Computational head injury models are promising tools for understanding and predicting traumatic brain injuries. However, most available head injury models are “average”models that employ a single set of head geometry (e.g., 50th-percentile U.S. male) without considering variability in these parameters across the human population. A significant variability of head shapes exists in U.S. Army soldiers, evident from the Anthropometric Survey of U.S. Army Personnel (ANSUR II). The objective of this study is to elucidate the effects of head shape on the predicted risk of traumatic brain injury from computational head injury models. Materials and Methods: Magnetic resonance imaging scans of 25 human subjects are collected. These images are registered to the standard MNI152 brain atlas, and the resulting transformation matrix components (called head shape parameters) are used to quantify head shapes of the subjects. A generative machine learning model is used to generate 25 additional head shape parameter datasets to augment our database. Head injury models are developed for these head shapes, and a rapid injurious head rotation event is simulated to obtain several brain injury predictor variables (BIPVs): Peak cumulative maximum principal strain (CMPS), average CMPS, and the volume fraction of brain exceeding an injurious CMPS threshold. A Gaussian process regression model is trained between head shape parameters and BIPVs, which is then used to study the relative sensitivity of the various BIPVs on individual head shape parameters. We distinguish head shape parameters into 2 types: Scaling components,, and that capture the breadth, length, and height of the head, respectively, and shearing components (, and) that capture the relative skewness of the head shape. Results: An overall positive correlation is evident between scaling components and BIPVs. Notably, a very high, positive correlation is seen between the BIPVs and the head volume. As an example, a 57% increase in peak CMPS was noted between the smallest and the largest investigated head volume parameters. The variation in shearing components, and on average does not cause notable changes in the BIPVs. From the Gaussian process regression model, all 3 BIPVs showed an increasing trend with each of the 3 scaling components, but the BIPVs are found to be most sensitive to the height dimension of the head. From the Sobol sensitivity analysis, the scaling parameter contributes nearly 60% to the total variance in peak and average CMPS; contributes approximately 20%, whereas contributes less than 5%. The remaining contribution is from the 6 shearing components. Unlike peak and average CMPS, the VF-CMPS BIPV is associated with relatively evenly distributed Sobol indices across the 3 scaling parameters. Furthermore, the contribution of shearing components on the total variance in this case is negligible. Conclusions: Head shape has a considerable influence on the injury predictions of computational head injury models. Available “average”head injury models based on a 50th-percentile U.S. male are likely associated with considerable uncertainty. In general, larger head sizes correspond to greater BIPV magnitudes, which point to potentially a greater injury risk under rapid neck rotation for people with larger heads. © 2024 The Association of Military Surgeons of the United States. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
Quantitative gradient recalled echo (qGRE) MRI enables in vivo measurement of pre-atrophic neurodegeneration in a mouse model of Alzheimer’s disease
(2024) NeuroImage, 298, art. no. 120794, .
Tomaszewski, M.R.a , Sukstanskii, A.L.b , Haley, H.a , Meng, X.a , Miller, C.O.a , Yablonskiy, D.A.b
a Translational Imaging Department, Merck & Co., Inc., Rahway, NJ, United States
b Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Robust methods are needed for preclinical evaluation of novel Alzheimer Disease (AD) therapies to accelerate drug discovery. Quantitative Gradient Recalled Echo (qGRE) MRI has shown promise to provide insight into neurodegeneration in AD prior to atrophy development in humans, highlighting areas of low neuronal density. In this study a novel qGRE method (20 echoes, TE=2-40ms) is shown to non-invasively measure the longitudinal neuronal loss in the hippocampus of a mouse model of AD tauopathy Tg4510. Tg4510 (n=10) and wild type (WT, n=6) mice underwent MRI (7T field strength) at 3-7 months old. 3D qGRE approach was used to generate brain-specific R2* maps free of magnetic field inhomogeneity artifacts. Light-sheet microscopy of the brains stained with NeuN and MBP served to visualize neuronal nuclei and myelin content respectively. Significant decrease in NeuN staining between 3mo and 5mo was observed in the hippocampus of Tg4510, validating the mouse AD model. Longitudinal analysis showed clear decreases in R2* metric of qGRE signal in the Tg4510 mice hippocampus undergoing neurodegeneration between 3 and 5 months old. Histogram analysis revealed an upward trend in patterns of low R2* value (Dark Matter, DM), and broadening of R2* distribution. These were quantified as significant increase in both DM Volume Fraction (DMVF) and R2* Standard Deviation (SD) in Tg4510 mice (p=0.004/p=0.016 DMVF/SD) but not in WT controls (p>0.25). Further monotonical increase was also observed in both metrics in time. A significant negative correlation was observed between the DMVF and myelin content (p=0.01, r=-0.76), suggesting sensitivity of the technique to the loss of myelinated axons. The presented qGRE technique, validated by histological measurements, can be readily applied as in vivo tool in preclinical models of neurodegeneration for pharmacodynamics and mechanism of action assessment. © 2024
Author Keywords
Alzheimer’s disease; MRI; Neurodegeneration; Neuronal density; QGRE; Tg4510
Document Type: Article
Publication Stage: Final
Source: Scopus
Characterization of Ptau181 Among a Diverse Community-Based Cohort: A HABS-HD Study
(2024) Journal of Alzheimer’s Disease, 100 (s1), pp. S63-S73.
Petersen, M.E.a b , Zhang, F.a b , Hall, J.R.a b , Julovich, D.a , Rissman, R.A.c , Meeker, K.L.a b , Phillips, N.a , Large, S.a , Ances, B.M.d , O’bryant, S.E.a b , HABS-HD Study Teame
a Institute for Translational Research, University of North Texas Health Science Center, Fort Worth, TX, United States
b Deparment of Family Medicine, University of North Texas Health Science Center, Fort Worth, TX, United States
c Keck School of Medicine of USC, Alzheimer’s Therapeutic Research Institute, San Diego, CA, United States
d Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Background: Examination of Alzheimer’s disease (AD) related biomarkers among diverse communities has remained limited. Objective: The aim of this study was to expand on prior work to provide a characterization of ptau181 among a diverse community sample. Consideration was taken regarding the impact of comorbidities on ptau181 levels including medical. Methods: 3,228 (n = 770 African American [AA], n = 1,231 Hispanic, and n = 1,227 non-Hispanic white [NHW]) Health and Aging Brain Study- Health Disparities (HABS-HD) participants were included in this study. ANCOVAs were conducted to examine differences in ptau181 levels across race and ethnic groups. Violin plots were also generated stratified by APOE ϵ4 carrier status, Amyloid PET positivity status, medical comorbidity (hypertension, dyslipidemia, chronic kidney disease [CKD], and diabetes) and by cognitive diagnosis. Results: Ptau181 levels were found to differ between Hispanics and NHW after covarying for age, sex, and APOE ϵ4 status. Amyloid PET positivity was associated with higher ptau181 levels across all groups. APOE ϵ4 positivity status was only significantly associated with ptau181 levels among AAs. Across all race and ethnic groups, those with a diagnosis of CKD had higher levels of ptau181. When stratified by cognitive diagnosis, cognitively unimpaired Hispanics had higher ptau181 if they also had a diagnosis of CKD or diabetes. p-values ≤0.01. Conclusions: Differences in ptau181 levels were shown in a diverse community sample. Medical comorbidities had a differing effect on ptau181 levels particularly among Hispanics even without cognitive impairment. Findings support the need for future work to consider comorbid conditions when examining the utility of ptau181. © 2024 – IOS Press. All rights reserved.
Author Keywords
Alzheimer’s disease; biomarkers; diverse; plasma; ptau181
Document Type: Article
Publication Stage: Final
Source: Scopus
Non-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage (NAVSaH): Protocol for a prospective, triple-blinded, randomized controlled trial
(2024) PLoS ONE, 19 (8), art. no. e0301154, .
Huguenard, A.a , Tan, G.b , Johnson, G.a , Adamek, M.c , Coxon, A.a , Kummer, T.d , Osbun, J.a , Vellimana, A.a , Limbrick, D., Jra , Zipfel, G.a , Brunner, P.a b , Leuthardt, E.a b c
a Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO, United States
b Department Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
c Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
d Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Background Inflammation has been implicated in driving the morbidity associated with subarachnoid hemorrhage (SAH). Despite understanding the important role of inflammation in morbidity following SAH, there is no current effective way to modulate this deleterious response. There is a critical need for a novel approach to immunomodulation that can be safely, rapidly, and effectively deployed in SAH patients. Vagus nerve stimulation (VNS) provides a non-pharmacologic approach to immunomodulation, with prior studies demonstrating VNS can reduce systemic inflammatory markers, and VNS has had early success treating inflammatory conditions such as arthritis, sepsis, and inflammatory bowel diseases. The aim of the Non-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage (NAVSaH) trial is to translate the use of non-invasive transcutaneous auricular VNS (taVNS) to spontaneous SAH, with our central hypothesis being that implementing taVNS in the acute period following spontaneous SAH attenuates the expected inflammatory response to hemorrhage and curtails morbidity associated with inflammatory-mediated clinical endpoints. Materials and methods The overall objectives for the NAHSaH trial are to 1) Define the impact that taVNS has on SAH-induced inflammatory markers in the plasma and cerebrospinal fluid (CSF), 2) Determine whether taVNS following SAH reduces radiographic vasospasm, and 3) Determine whether taVNS following SAH reduces chronic hydrocephalus. Following presentation to a single enrollment site, enrolled SAH patients are randomly assigned twice daily treatment with either taVNS or sham stimulation for the duration of their intensive care unit stay. Blood and CSF are drawn before initiation of treatment sessions, and then every three days during a patient’s hospital stay. Primary endpoints include change in the inflammatory cytokine TNF-α in plasma and cerebrospinal fluid between day 1 and day 13, rate of radiographic vasospasm, and rate of requirement for long-term CSF diversion via a ventricular shunt. Secondary outcomes include exploratory analyses of a panel of additional cytokines, number and type of hospitalized acquired infections, duration of external ventricular drain in days, interventions required for vasospasm, continuous physiology data before, during, and after treatment sessions, hospital length of stay, intensive care unit length of stay, and modified Rankin Scale score (mRS) at admission, discharge, and each at follow-up appointment for up to two years following SAH. Discussion Inflammation plays a central role in morbidity following SAH. This NAVSaH trial is innovative because it diverges from the pharmacologic status quo by harnessing a novel non-invasive neuromodulatory approach and its known anti-inflammatory effects to alter the pathophysiology of SAH. The investigation of a new, effective, and rapidly deployable intervention in SAH offers a new route to improve outcomes following SAH. © 2024 Huguenard et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Document Type: Article
Publication Stage: Final
Source: Scopus
The Influence of Personality Traits on Driving Behaviors in Preclinical Alzheimer Disease
(2024) Alzheimer Disease and Associated Disorders, 38 (3), pp. 241-248.
Aschenbrenner, A.J.a , Carr, D.B.a b , Benzinger, T.L.S.c , Morris, J.C.a , Babulal, G.M.a d e f
a Departments of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Departments of Medicine and Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Departments of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Institute of Public Health, Washington University School of Medicine, St. Louis, MO, United States
e Department of Clinical Research and Leadership, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
f Department of Psychology, Faculty of Humanities, University of Johannesburg, South Africa
Abstract
Introduction: Alzheimer disease (AD) has a long preclinical phase in which AD pathology is accumulating without detectable clinical symptoms. It is critical to identify participants in this preclinical phase as early as possible since treatment plans may be more effective in this stage. Monitoring for changes in driving behavior, as measured with GPS sensors, has been explored as a low-burden, easy-To-Administer method for detecting AD risk. However, driving is a complex, multifaceted process that is likely influenced by other factors, including personality traits, that may change in preclinical AD. Methods: We examine the moderating influence of neuroticism and conscientiousness on longitudinal changes in driving behavior in a sample of 203 clinically normal older adults who are at varying risk of developing AD. Results: Neuroticism moderated rates of change in the frequency of speeding as well as the number of trips taken at night. Conscientiousness moderated rates of change in typical driving space. Conclusions: Personality traits change in early AD and also influence driving behaviors. Studies that seek to utilize naturalistic driving behavior to establish AD risk need to accommodate interpersonal differences, of which personality traits are one of many possible factors. Future studies should explicitly establish how much benefit is provided by including personality traits in predictive models of AD progression. © 2024 Wolters Kluwer Health, Inc. All rights reserved.
Author Keywords
Alzheimer disease; naturalistic driving; personality
Document Type: Article
Publication Stage: Final
Source: Scopus
Alzheimer’s Disease-Related Analytes Amyloid-β and Tau in Perilymph: Correlation With Patient Age and Cognitive Score
(2024) Otolaryngology – Head and Neck Surgery (United States), .
Walia, A.a , Shew, M.A.a , Durakovic, N.a , Herzog, J.A.a , Cirrito, J.R.b , Yuede, C.M.b , Wick, C.C.a , Manis, M.b , Holtzman, D.M.b c , Buchman, C.A.a , Rutherford, M.A.a
a Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine in St Louis, St Louis, MO, United States
b Department of Neurology, Washington University School of Medicine in St Louis, St Louis, MO, United States
c Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Objective: To describe the collection methods for perilymph fluid biopsy during cochlear implantation, detect levels of amyloid β 42 and 40 (Aβ42 and Aβ40), and total tau (tTau) analytes with a high-precision assay, to compare these levels with patient age and Montreal Cognitive Assessment (MoCA) scores, and explore potential mechanisms and relationships with otic pathology. Study Design: Prospective study. Setting: Tertiary referral center. Methods: Perilymph was collected from 25 patients using polyimide tubing to avoid amyloid adherence to glass, and analyzed with a single-molecule array advanced digital enzyme-linked immunosorbent assay platform for Aβ40, Aβ42, and tTau. Cognition was assessed by MoCA. Results: Perilymph volumes ranged from ∼1 to 13 µL, with analyte concentrations spanning 2.67 to 1088.26 pg/mL. All samples had detectable levels of tTau, Aβ40, and Aβ42, with a significant positive correlation between Aβ42 and Aβ40 levels. Levels of Aβ42, Aβ40, and tTau were positively correlated with age, while MoCA scores were inversely correlated with age. tTau and Aβ42/Aβ40-ratios were significantly correlated with MoCA scores. Conclusion: Alzheimer’s disease-associated peptides Aβ42, Aβ40, and tau analytes are detectable in human perilymph at levels approximately 10-fold lower than those found in cerebrospinal fluid (CSF). These species increase with age and correlate with cognitive impairment indicators, suggesting their potential utility as biomarkers for cognitive impairment in patients undergoing cochlear implantation. Future research should investigate the origin of these analytes in the perilymph and their potential links to inner ear pathologies and hearing loss, as well as their relationships to CSF and plasma levels in individuals. © 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.
Author Keywords
Alzheimer’s disease; amyloid; Aβ40; Aβ42; cochlear implantation; cognition; MoCA; perilymph; tau
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Multi-peptide characterization of plasma neurofilament light chain in preclinical and mild Alzheimer’s disease
(2024) Brain Communications, 6 (4), art. no. fcae247, .
Coulton, J.B.a b , He, Y.a b , Barthélemy, N.R.a b , Jiang, H.a c d , Holtzman, D.M.a c d , Bateman, R.J.a b c d
a Department of Neurology, Washington University, School of Medicine, St. Louis, MO 63110, United States
b Tracy Family SILQ Center, Washington University, School of Medicine, St. Louis, MO 63110, United States
c Knight Alzheimer’s Disease Research Center, Washington University, School of Medicine, St. Louis, MO 63108, United States
d Hope Center for Neurological Disorders, Washington University, School of Medicine, St. Louis, MO 63110, United States
Abstract
Although neurofilament light chain is a well-known marker of neuronal damage, its characterization at the proteoform level is underdeveloped. Here, we describe a new method to profile and quantify neurofilament light chain in plasma at the peptide level, using three in-house monoclonal antibodies targeting distinct protein domains and nano-liquid chromatography coupled to high-resolution tandem mass spectrometry. This study profiled and compared plasma neurofilament light chain to CSF in 102 older individuals (73.9 ± 6.3 years old), 37 of which had a clinical dementia rating greater than 0. We observed elevated neurofilament light chain in preclinical Alzheimer’s disease plasma for two measures (NfL101 and NfL324) and CSF for seven measures (NfL92, NfL101, NfL117, NfL137, NfL148, NfL165 and NfL530). We found five plasma peptides (NfL92, NfL101, NfL117, NfL324 and NfL530) significantly associated with age and two (NfL148 and NfL324) with body mass index. © The Author(s) 2024.
Author Keywords
biomarkers; immunoprecipitation; mass spectrometry; neurodegeneration; neurofilament
Document Type: Article
Publication Stage: Final
Source: Scopus
Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APPSAA knock-in mouse model of Alzheimer’s disease
(2024) Alzheimer’s and Dementia, .
Norambuena, A.a , Sagar, V.K.a b , Wang, Z.c , Raut, P.a , Feng, Z.c , Wallrabe, H.a b , Pardo, E.a , Kim, T.a , Alam, S.R.a b , Hu, S.c , Periasamy, A.a b , Bloom, G.S.a d e
a Department of Biology, University of Virginia, Charlottesville, VA, United States
b W.M. Keck Center for Cellular Imaging, University of Virginia, Charlottesville, VA, United States
c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
d Department of Cell Biology, University of Virginia, Charlottesville, VA, United States
e Department of Neuroscience, University of Virginia, Charlottesville, VA, United States
Abstract
INTRODUCTION: Reduced brain energy metabolism, mammalian target of rapamycin (mTOR) dysregulation, and extracellular amyloid beta (Aβ) oligomer (xcAβO) buildup are some well-known Alzheimer’s disease (AD) features; how they promote neurodegeneration is poorly understood. We previously reported that xcAβOs inhibit nutrient-induced mitochondrial activity (NiMA) in cultured neurons. We now report NiMA disruption in vivo. METHODS: Brain energy metabolism and oxygen consumption were recorded in heterozygous amyloid precursor protein knock-in (APPSAA) mice using two-photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy. RESULTS: NiMA is inhibited in APPSAA mice before other defects are detected in these Aβ-producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. Glycogen synthase kinase 3 (GSK3β) signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3β with TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APPSAA mice. DISCUSSION: NiMA disruption in vivo occurs before plaques, neuroinflammation, and cognitive decline in APPSAA mice, and may represent an early stage in human AD. Highlights: Amyloid beta blocks communication between lysosomes and mitochondria in vivo. Nutrient-induced mitochondrial activity (NiMA) is disrupted long before the appearance of Alzheimer’s disease (AD) histopathology in heterozygous amyloid precursor protein knock-in (APPSAA/+) mice. NiMA is disrupted long before learning and memory deficits in APPSAA/+ mice. Pharmacological interventions can rescue AD-related NiMA disruption in vivo. © 2024 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
amino acids; brain metabolism; insulin; mammalian target of rapamycin; tau
Document Type: Article
Publication Stage: Article in Press
Source: Scopus