Publications by authors named "Christopher T Whitlow"

89 Publications

Relationship Between Time-Weighted Head Impact Exposure on Directional Changes in Diffusion Imaging in Youth Football Players.

Ann Biomed Eng 2021 Oct 21;49(10):2852-2862. Epub 2021 Sep 21.

Department of Biomedical Engineering, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Approximately 3.5 million youth and adolescents in the US play football, a sport with one of the highest rates of concussion. Repeated subconcussive head impact exposure (HIE) may lead to negative neurological sequelae. To understand HIE as an independent predictive variable, quantitative cumulative kinematic metrics have been developed to capture the volume (i.e., number), severity (i.e., magnitude), and frequency (i.e., time-weighting by the interval between head impacts). In this study, time-weighted cumulative HIE metrics were compared with directional changes in diffusion tensor imaging (DTI) metrics. Changes in DTI conducted on a per-season, per-player basis were assessed as a dependent variable. Directional changes were defined separately as increases and decreases in the number of abnormal voxels relative to non-contact sport controls. Biomechanical and imaging data from 117 athletes (average age 11.9 ± 1.0 years) enrolled in this study was analyzed. Cumulative HIE metrics were more strongly correlated with increases in abnormal voxels than decreases in abnormal voxels. Additionally, across DTI sub-measures, increases and decreases in mean diffusivity (MD) had the strongest relationships with HIE metrics (increases in MD: average R = 0.1753, average p = 0.0002; decreases in MD: average R = 0.0997, average p = 0.0073). This encourages further investigation into the physiological phenomena represented by directional changes.
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http://dx.doi.org/10.1007/s10439-021-02862-4DOI Listing
October 2021

Associations among vascular risk factors, neuroimaging biomarkers, and cognition: Preliminary analyses from the Multi-Ethnic Study of Atherosclerosis (MESA).

Alzheimers Dement 2021 Sep 5. Epub 2021 Sep 5.

Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

Introduction: Little is known about how antecedent vascular risk factor (VRF) profiles impact late-life brain health.

Methods: We examined baseline VRFs, and cognitive testing and neuroimaging measures (β-amyloid [Aβ] PET, MRI) in a diverse longitudinal cohort (N = 159; 50% African-American, 50% White) from Wake Forest's Multi-Ethnic Study of Atherosclerosis Core.

Results: African-Americans exhibited greater baseline Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE), Framingham stroke risk profile (FSRP), and atherosclerotic cardiovascular disease risk estimate (ASCVD) scores than Whites. We observed no significant racial differences in Aβ positivity, cortical thickness, or white matter hyperintensity (WMH) volume. Higher baseline VRF scores were associated with lower cortical thickness and greater WMH volume, and FSRP and CAIDE were associated with Aβ. Aβ was cross-sectionally associated with cognition, and all imaging biomarkers were associated with greater 6-year cognitive decline.

Discussion: Results suggest the convergence of multiple vascular and Alzheimer's processes underlying neurodegeneration and cognitive decline.
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http://dx.doi.org/10.1002/alz.12429DOI Listing
September 2021

The Acute Effects of Time-Varying Caloric Vestibular Stimulation as Assessed With fMRI.

Front Syst Neurosci 2021 9;15:648928. Epub 2021 Aug 9.

Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, United States.

We describe preliminary results from the application of time-varying caloric vestibular stimulation (tvCVS) to volunteers during a continuous blood oxygen level dependent (BOLD) functional MRI (fMRI) acquisition, recording baseline, during-tvCVS and post-tvCVS epochs. The modifications necessary to enable the use of this novel device in a 3-Tesla magnetic field are discussed. Independent component analysis (ICA) was used as a model-free method to highlight spatially and temporally coherent brain networks. The ICA results are consistent with tvCVS induction being mediated principally by thermoconvection in the vestibular labyrinth and not by direct thermal effects. The activation of hub networks identified by ICA is consistent with the concept of sensory neuromodulation, which posits that a modulatory signal introduced to a sensory organ is able to traverse the regions innervated (directly and indirectly) by that organ, while being transformed so as to be "matched" to regional neuronal dynamics. The data suggest that regional neurovascular coupling and a systemic cerebral blood flow component account for the BOLD contrast observed. The ability to modulate cerebral hemodynamics is of significant interest. The implications of these initial findings for the use of tvCVS therapeutically are discussed.
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http://dx.doi.org/10.3389/fnsys.2021.648928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381736PMC
August 2021

Comparing data-driven and hypothesis-driven MRI-based predictors of cognitive impairment in individuals from the Atherosclerosis Risk in Communities (ARIC) study.

Alzheimers Dement 2021 Jul 26. Epub 2021 Jul 26.

Divison of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

Introduction: A data-driven index of dementia risk based on magnetic resonance imaging (MRI), the Alzheimer's Disease Pattern Similarity (AD-PS) score, was estimated for participants in the Atherosclerosis Risk in Communities (ARIC) study.

Methods: AD-PS scores were generated for 839 cognitively non-impaired individuals with a mean follow-up of 4.86 years. The scores and a hypothesis-driven volumetric measure based on several brain regions susceptible to AD were compared as predictors of incident cognitive impairment in different settings.

Results: Logistic regression analyses suggest the data-driven AD-PS scores to be more predictive of incident cognitive impairment than its counterpart. Both biomarkers were more predictive of incident cognitive impairment in participants who were White, female, and apolipoprotein E gene (APOE) ε4 carriers. Random forest analyses including predictors from different domains ranked the AD-PS scores as the most relevant MRI predictor of cognitive impairment.

Conclusions: Overall, the AD-PS scores were the stronger MRI-derived predictors of incident cognitive impairment in cognitively non-impaired individuals.
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http://dx.doi.org/10.1002/alz.12427DOI Listing
July 2021

MEGnet: Automatic ICA-based artifact removal for MEG using spatiotemporal convolutional neural networks.

Neuroimage 2021 11 16;241:118402. Epub 2021 Jul 16.

Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, United States; Department of Radiology, UT Southwestern Medical Center, Dallas, TX, United States; Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, United States. Electronic address:

Magnetoencephalography (MEG) is a functional neuroimaging tool that records the magnetic fields induced by neuronal activity; however, signal from non-neuronal sources can corrupt the data. Eye-blinks, saccades, and cardiac activity are three of the most common sources of non-neuronal artifacts. They can be measured by affixing eye proximal electrodes, as in electrooculography (EOG), and chest electrodes, as in electrocardiography (ECG), however this complicates imaging setup, decreases patient comfort, and can induce further artifacts from movement. This work proposes an EOG- and ECG-free approach to identify eye-blinks, saccades, and cardiac activity signals for automated artifact suppression. The contribution of this work is three-fold. First, using a data driven, multivariate decomposition approach based on Independent Component Analysis (ICA), a highly accurate artifact classifier is constructed as an amalgam of deep 1-D and 2-D Convolutional Neural Networks (CNNs) to automate the identification and removal of ubiquitous whole brain artifacts including eye-blink, saccade, and cardiac artifacts. The specific architecture of this network is optimized through an unbiased, computer-based hyperparameter random search. Second, visualization methods are applied to the learned abstraction to reveal what features the model uses and to bolster user confidence in the model's training and potential for generalization. Finally, the model is trained and tested on both resting-state and task MEG data from 217 subjects, and achieves a new state-of-the-art in artifact detection accuracy of 98.95% including 96.74% sensitivity and 99.34% specificity on the held out test-set. This work automates MEG processing for both clinical and research use, adapts to the acquired acquisition time, and can obviate the need for EOG or ECG electrodes for artifact detection.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118402DOI Listing
November 2021

Feasibility and Biological Activity of a Ketogenic/Intermittent-Fasting Diet in Patients With Glioma.

Neurology 2021 08 7;97(9):e953-e963. Epub 2021 Jul 7.

From the Departments of Neurology (K.C.S., J.O.B., L.B., E.H.K., M.C.C., R.E.S.), Oncology (K.C.S., J.O.B.), Neurosurgery (K.C.S., J.O.B.), and Radiology (A.B., P.B.B.) and Institute for Clinical and Translational Research (B.H.-B., D.V.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Biostatistics and Data Science (F.-C.H., C.T.W.), Clinical Research Unit (L.E.), Department of Radiology (C.T.W.), Department of Biomedical Engineering (C.T.W.), Clinical and Translational Science Institute (C.T.W.), Department of Neurology (R.E.S.), and Department of Oncology (R.E.S.), Wake Forest School of Medicine, Winston-Salem, NC; and Sir Peter Mansfield Imaging Centre (A.B.), School of Physics and Astronomy, University of Nottingham, UK.

Objective: To examine the feasibility, safety, systemic biological activity, and cerebral activity of a ketogenic dietary intervention in patients with glioma.

Methods: Twenty-five patients with biopsy-confirmed World Health Organization grade 2 to 4 astrocytoma with stable disease after adjuvant chemotherapy were enrolled in an 8-week Glioma Atkins-Based Diet (GLAD). GLAD consisted of 2 fasting days (calories <20% calculated estimated needs) interleaved between 5 modified Atkins diet days (net carbohydrates ≤20 g/d) each week. The primary outcome was dietary adherence by food records. Markers of systemic and cerebral activity included weekly urine ketones, serum insulin, glucose, hemoglobin A1c, insulin-like growth factor-1, and magnetic resonance spectroscopy at baseline and week 8.

Results: Twenty-one patients (84%) completed the study. Eighty percent of patients reached ≥40 mg/dL urine acetoacetate during the study. Forty-eight percent of patients were adherent by food record. The diet was well tolerated, with two grade 3 adverse events (neutropenia, seizure). Measures of systemic activity, including hemoglobin A1c, insulin, and fat body mass, decreased significantly, while lean body mass increased. Magnetic resonance spectroscopy demonstrated increased ketone concentrations (β-hydroxybutyrate [bHB] and acetone) in both lesional and contralateral brain compared to baseline. Average ketonuria correlated with cerebral ketones in lesional (tumor) and contralateral brain (bHB = 0.52, = 0.05). Subgroup analysis of isocitrate dehydrogenase-mutant glioma showed no differences in cerebral metabolites after controlling for ketonuria.

Conclusion: The GLAD dietary intervention, while demanding, produced meaningful ketonuria and significant systemic and cerebral metabolic changes in participants. Ketonuria in participants correlated with cerebral ketone concentration and appears to be a better indicator of systemic activity than patient-reported food records.

Trial Registration Information: ClinicalTrials.gov Identifier: NCT02286167.
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http://dx.doi.org/10.1212/WNL.0000000000012386DOI Listing
August 2021

Relationship Between Cerebrovascular Reactivity and Cognition Among People With Risk of Cognitive Decline.

Front Physiol 2021 31;12:645342. Epub 2021 May 31.

Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States.

Vascular risk factors (e.g., obesity and hypertension) are associated with cerebral small vessel disease, Alzheimer's disease (AD) pathology, and dementia. Reduced perfusion may reflect the impaired ability of blood vessels to regulate blood flow in reaction to varying circumstances such as hypercapnia (increased end-tidal partial pressures of CO). It has been shown that cerebrovascular reactivity (CVR) measured with blood-oxygen-level-dependent (BOLD) MRI is correlated with cognitive performance and alterations of CVR may be an indicator of vascular disfunction leading to cognitive decline. However, the underlying mechanism of CVR alterations in BOLD signal may not be straight-forward because BOLD signal is affected by multiple physiological parameters, such as cerebral blood flow (CBF), cerebral blood volume, and oxygen metabolism. Arterial spin labeling (ASL) MRI quantitatively measures blood flow in the brain providing images of local CBF. Therefore, in this study, we measured CBF and its changes using a dynamic ASL technique during a hypercapnia challenge and tested if CBF or CVR was related to cognitive performance using the Mini-mental state examination (MMSE) score. Seventy-eight participants underwent cognitive testing and MRI including ASL during a hypercapnia challenge with a RespirAct computer-controlled gas blender, targeting 10 mmHg higher end-tidal CO level than the baseline while end-tidal O level was maintained. Pseudo-continuous ASL (PCASL) was collected during a 2-min baseline and a 2-min hypercapnic period. CVR was obtained by calculating a percent change of CBF per the end-tidal CO elevation in mmHg between the baseline and the hypercapnic challenge. Multivariate regression analyses demonstrated that baseline resting CBF has no significant relationship with MMSE, while lower CVR in the whole brain gray matter ( = 0.689, = 0.005) and white matter ( = 0.578, = 0.016) are related to lower MMSE score. In addition, region of interest (ROI) based analysis showed positive relationships between MMSE score and CVR in 26 out of 122 gray matter ROIs.
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http://dx.doi.org/10.3389/fphys.2021.645342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201407PMC
May 2021

Analysis of longitudinal head impact exposure and white matter integrity in returning youth football players.

J Neurosurg Pediatr 2021 Jun 15:1-10. Epub 2021 Jun 15.

Departments of1Biomedical Engineering.

Objective: The objective of this study was to characterize changes in head impact exposure (HIE) across multiple football seasons and to determine whether changes in HIE correlate with changes in imaging metrics in youth football players.

Methods: On-field head impact data and pre- and postseason imaging data, including those produced by diffusion tensor imaging (DTI), were collected from youth football athletes with at least two consecutive seasons of data. ANCOVA was used to evaluate HIE variations (number of impacts, peak linear and rotational accelerations, and risk-weighted cumulative exposure) by season number. DTI scalar metrics, including fractional anisotropy, mean diffusivity, and linear, planar, and spherical anisotropy coefficients, were evaluated. A control group was used to determine the number of abnormal white matter voxels, which were defined as 2 standard deviations above or below the control group mean. The difference in the number of abnormal voxels between consecutive seasons was computed for each scalar metric and athlete. Linear regression analyses were performed to evaluate relationships between changes in HIE metrics and changes in DTI scalar metrics.

Results: There were 47 athletes with multiple consecutive seasons of HIE, and corresponding imaging data were available in a subsample (n = 19) of these. Increases and decreases in HIE metrics were observed among individual athletes from one season to the next, and no significant differences (all p > 0.05) in HIE metrics were observed by season number. Changes in the number of practice impacts, 50th percentile impacts per practice session, and 50th percentile impacts per session were significantly positively correlated with changes in abnormal voxels for all DTI metrics.

Conclusions: These results demonstrate a significant positive association between changes in HIE metrics and changes in the numbers of abnormal voxels between consecutive seasons of youth football. Reducing the number and frequency of head impacts, especially during practice sessions, may decrease the number of abnormal imaging findings from one season to the next in youth football.
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http://dx.doi.org/10.3171/2021.1.PEDS20586DOI Listing
June 2021

Regional White Matter Diffusion Changes Associated with the Cumulative Tensile Strain and Strain Rate in Nonconcussed Youth Football Players.

J Neurotrauma 2021 Oct 3;38(19):2763-2771. Epub 2021 Sep 3.

University of Texas Southwestern Medical Center, Dallas, Texas, USA.

The purpose of this study is to assess the relationship between regional white matter diffusion imaging changes and finite element strain measures in nonconcussed youth football players. Pre- and post-season diffusion-weighted imaging was performed in 102 youth football subject-seasons, in which no concussions were diagnosed. The diffusion data were normalized to the IXI template. Percent change in fractional anisotropy (%ΔFA) images were generated. Using data from the head impact telemetry system, the cumulative maximum principal strain one times strain rate (CMPS1 SR), a measure of the cumulative tensile brain strain and strain rate for one season, was calculated for each subject. Two linear regression analyses were performed to identify significant positive or inverse relationships between CMPS1 SR and %ΔFA within the international consortium for brain mapping white matter mask. Age, body mass index, days between pre- and post-season imaging, previous brain injury, attention disorder diagnosis, and imaging protocol were included as covariates. False discovery rate correction was used with corrected alphas of 0.025 and voxel thresholds of zero. Controlling for all covariates, a significant, positive linear relationship between %ΔFA and CMPS1 SR was identified in the bilateral cingulum, fornix, internal capsule, external capsule, corpus callosum, corona radiata, corticospinal tract, cerebral and middle cerebellar peduncle, superior longitudinal fasciculus, and right superior fronto-occipital fasciculus. analyses further demonstrated significant %ΔFA differences between high-strain football subjects and noncollision control athletes, no significant %ΔFA differences between low-strain subjects and noncollision control athletes, and that CMPS1 SR significantly explained more %ΔFA variance than number of head impacts alone.
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http://dx.doi.org/10.1089/neu.2020.7580DOI Listing
October 2021

Multi-Omics Analysis of Brain Metastasis Outcomes Following Craniotomy.

Front Oncol 2020 6;10:615472. Epub 2021 Apr 6.

Department of Medicine (Hematology & Oncology), Wake Forest School of Medicine, Winston-Salem, NC, United States.

Background: The incidence of brain metastasis continues to increase as therapeutic strategies have improved for a number of solid tumors. The presence of brain metastasis is associated with worse prognosis but it is unclear if distinctive biomarkers can separate patients at risk for CNS related death.

Methods: We executed a single institution retrospective collection of brain metastasis from patients who were diagnosed with lung, breast, and other primary tumors. The brain metastatic samples were sent for RNA sequencing, proteomic and metabolomic analysis of brain metastasis. The primary outcome was distant brain failure after definitive therapies that included craniotomy resection and radiation to surgical bed. Novel prognostic subtypes were discovered using transcriptomic data and sparse non-negative matrix factorization.

Results: We discovered two molecular subtypes showing statistically significant differential prognosis irrespective of tumor subtype. The median survival time of the good and the poor prognostic subtypes were 7.89 and 42.27 months, respectively. Further integrated characterization and analysis of these two distinctive prognostic subtypes using transcriptomic, proteomic, and metabolomic molecular profiles of patients identified key pathways and metabolites. The analysis suggested that immune microenvironment landscape as well as proliferation and migration signaling pathways may be responsible to the observed survival difference.

Conclusion: A multi-omics approach to characterization of brain metastasis provides an opportunity to identify clinically impactful biomarkers and associated prognostic subtypes and generate provocative integrative understanding of disease.
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http://dx.doi.org/10.3389/fonc.2020.615472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056216PMC
April 2021

Mapping default mode connectivity alterations following a single season of subconcussive impact exposure in youth football.

Hum Brain Mapp 2021 Jun 18;42(8):2529-2545. Epub 2021 Mar 18.

Advanced Neuroscience Imaging Research (ANSIR) Laboratory, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Repetitive head impact (RHI) exposure in collision sports may contribute to adverse neurological outcomes in former players. In contrast to a concussion, or mild traumatic brain injury, "subconcussive" RHIs represent a more frequent and asymptomatic form of exposure. The neural network-level signatures characterizing subconcussive RHIs in youth collision-sport cohorts such as American Football are not known. Here, we used resting-state functional MRI to examine default mode network (DMN) functional connectivity (FC) following a single football season in youth players (n = 50, ages 8-14) without concussion. Football players demonstrated reduced FC across widespread DMN regions compared with non-collision sport controls at postseason but not preseason. In a subsample from the original cohort (n = 17), players revealed a negative change in FC between preseason and postseason and a positive and compensatory change in FC during the offseason across the majority of DMN regions. Lastly, significant FC changes, including between preseason and postseason and between in- and off-season, were specific to players at the upper end of the head impact frequency distribution. These findings represent initial evidence of network-level FC abnormalities following repetitive, non-concussive RHIs in youth football. Furthermore, the number of subconcussive RHIs proved to be a key factor influencing DMN FC.
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http://dx.doi.org/10.1002/hbm.25384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090779PMC
June 2021

Brain cell-derived exosomes in plasma serve as neurodegeneration biomarkers in male cynomolgus monkeys self-administrating oxycodone.

EBioMedicine 2021 Jan 6;63:103192. Epub 2021 Jan 6.

Department of Cancer Biology, Wake Forest Baptist Medical Center, United States; Comprehensive Cancer Center, Wake Forest Baptist Health, United States; Center for Research on Substance Use and Addiction, Wake Forest School of Medicine, United States; Department of Urology, Wake Forest School of Medicine, Winston-Salem, NC, United States. Electronic address:

Background: The United States is currently facing an opioid crisis. Novel tools to better comprehend dynamic molecular changes in the brain associated with the opioid abuse are limited. Recent studies have suggested the usefulness of plasma exosomes in better understanding CNS disorders. However, no study has ever characterized exosomes (small extracellular vesicles of endocytic origin) secreted by brain cells to understand the potential neurodegenerative effects of long-term oxycodone self-administration (SA).

Methods: MRI of Cynomolgus monkeys (Macaca fascicularis) was performed to assess alterations in gray matter volumes with oxycodone SA. We isolated total exosomes (TE) from the plasma of these monkeys; from TE, we pulled-out neuron-derived exosomes (NDE), astrocytes-derived exosomes (ADE), and microglia-derived exosomes (MDE) using surface biomarkers L1CAM (L1 cell adhesion molecule), GLAST (Glutamate aspartate transporter) and TMEM119 (transmembrane protein119), respectively.

Findings: We observed a significantly lower gray matter volume of specific lobes of the brain (frontal and parietal lobes, and right putamen) in monkeys with ∼3 years of oxycodone SA compared to controls. Higher expression of neurodegenerative biomarkers (NFL and α-synuclein) correlates well with the change in brain lobe volumes in control and oxycodone SA monkeys. We also identified a strong effect of oxycodone SA on the loading of specific miRNAs and proteins associated with neuro-cognitive disorders. Finally, exosomes subpopulation from oxycodone SA group activated NF-κB activity in THP1- cells.

Interpretation: These results provide evidence for the utility of brain cells-derived exosomes from plasma in better understanding and predicting the pro-inflammatory and neurodegenerative consequence of oxycodone SA.

Funding: NIH.
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http://dx.doi.org/10.1016/j.ebiom.2020.103192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804975PMC
January 2021

Diet, psychosocial stress, and Alzheimer's disease-related neuroanatomy in female nonhuman primates.

Alzheimers Dement 2021 05 3;17(5):733-744. Epub 2020 Dec 3.

Department of Pathology/Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

Introduction: Associations between diet, psychosocial stress, and neurodegenerative disease, including Alzheimer's disease (AD), have been reported, but causal relationships are difficult to determine in human studies.

Methods: We used structural magnetic resonance imaging in a well-validated non-human primate model of AD-like neuropathology to examine the longitudinal effects of diet (Mediterranean vs Western) and social subordination stress on brain anatomy, including global volumes, cortical thicknesses and volumes, and 20 individual regions of interest (ROIs).

Results: Western diet resulted in greater cortical thicknesses, total brain volumes, and gray matter, and diminished cerebrospinal fluid and white matter volumes. Socially stressed subordinates had smaller whole brain volumes but larger ROIs relevant to AD than dominants.

Discussion: The observation of increased size of AD-related brain areas is consistent with similar reports of mid-life volume increases predicting increased AD risk later in life. While the biological mechanisms underlying the findings require future investigation, these observations suggest that Western diet and psychosocial stress instigate pathologic changes that increase risk of AD-associated neuropathology, whereas the Mediterranean diet may protect the brain.
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http://dx.doi.org/10.1002/alz.12232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119381PMC
May 2021

Brain Strain: Computational Model-Based Metrics for Head Impact Exposure and Injury Correlation.

Ann Biomed Eng 2021 Mar 30;49(3):1083-1096. Epub 2020 Nov 30.

Department of Biomedical Engineering, Wake Forest School of Medicine, 575 N. Patterson Avenue, Suite 530, Winston-Salem, NC, 27101, USA.

Athletes participating in contact sports are exposed to repetitive subconcussive head impacts that may have long-term neurological consequences. To better understand these impacts and their effects, head impacts are often measured during football to characterize head impact exposure and estimate injury risk. Despite widespread use of kinematic-based metrics, it remains unclear whether any single metric derived from head kinematics is well-correlated with measurable changes in the brain. This shortcoming has motivated the increasing use of finite element (FE)-based metrics, which quantify local brain deformations. Additionally, quantifying cumulative exposure is of increased interest to examine the relationship to brain changes over time. The current study uses the atlas-based brain model (ABM) to predict the strain response to impacts sustained by 116 youth football athletes and proposes 36 new, or derivative, cumulative strain-based metrics that quantify the combined burden of head impacts over the course of a season. The strain-based metrics developed and evaluated for FE modeling and presented in the current study present potential for improved analytics over existing kinematically-based and cumulative metrics. Additionally, the findings highlight the importance of accounting for directional dependence and expand the techniques to explore spatial distribution of the strain response throughout the brain.
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http://dx.doi.org/10.1007/s10439-020-02685-9DOI Listing
March 2021

Misleading Public Statements About COVID-19.

J Am Coll Radiol 2021 01 24;18(1 Pt A):6-7. Epub 2020 Oct 24.

Professor, Departments of Radiology, Biomedical Engineering, and Biostatistics and Data Science; Chief of Neuroradiology; Vice Chair of Informatics, Department of Radiology, Wake Forest School of Medicine, Winston-Salem, North Carolina.

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http://dx.doi.org/10.1016/j.jacr.2020.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585358PMC
January 2021

Non-Human Primates Receiving High-Dose Total-Body Irradiation are at Risk of Developing Cerebrovascular Injury Years Postirradiation.

Radiat Res 2020 09;194(3):277-287

Departments of Pathology, Section on Comparative Medicine.

Nuclear accidents and acts of terrorism have the potential to expose thousands of people to high-dose total-body iradiation (TBI). Those who survive the acute radiation syndrome are at risk of developing chronic, degenerative radiation-induced injuries [delayed effects of acute radiation (DEARE)] that may negatively affect quality of life. A growing body of literature suggests that the brain may be vulnerable to radiation injury at survivable doses, yet the long-term consequences of high-dose TBI on the adult brain are unclear. Herein we report the occurrence of lesions consistent with cerebrovascular injury, detected by susceptibility-weighted magnetic resonance imaging (MRI), in a cohort of non-human primate [(NHP); rhesus macaque, Macaca mulatta] long-term survivors of high-dose TBI (1.1-8.5 Gy). Animals were monitored longitudinally with brain MRI (approximately once every three years). Susceptibility-weighted images (SWI) were reviewed for hypointensities (cerebral microbleeds and/or focal necrosis). SWI hypointensities were noted in 13% of irradiated NHP; lesions were not observed in control animals. A prior history of exposure was correlated with an increased risk of developing a lesion detectable by MRI (P = 0.003). Twelve of 16 animals had at least one brain lesion present at the time of the first MRI evaluation; a subset of animals (n = 7) developed new lesions during the surveillance period (3.7-11.3 years postirradiation). Lesions occurred with a predilection for white matter and the gray-white matter junction. The majority of animals with lesions had one to three SWI hypointensities, but some animals had multifocal disease (n = 2). Histopathologic evaluation of deceased animals within the cohort (n = 3) revealed malformation of the cerebral vasculature and remodeling of the blood vessel walls. There was no association between comorbid diabetes mellitus or hypertension with SWI lesion status. These data suggest that long-term TBI survivors may be at risk of developing cerebrovascular injury years after irradiation.
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http://dx.doi.org/10.1667/RADE-20-00051.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583660PMC
September 2020

Predictors of Adverse Radiation Effect in Brain Metastasis Patients Treated With Stereotactic Radiosurgery and Immune Checkpoint Inhibitor Therapy.

Int J Radiat Oncol Biol Phys 2020 09 29;108(1):295-303. Epub 2020 Jun 29.

Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, North Carolina.

Purpose: Immune checkpoint inhibitor (ICI) therapy has recently been found to improve survival in patients with a number of cancers, including those with metastatic disease. There is an association of adverse radiation effect (ARE) in patients with brain metastases who have been treated with stereotactic radiosurgery (SRS) and ICIs.

Methods And Materials: Single-institution retrospective review identified 1118 brain metastases treated with SRS between 2013 and 2018 that had received ICI therapy and 886 metastases that did not receive ICI. Toxicity grading was done via the Common Terminology Criteria for Adverse Events v4.0 grading criteria. Cumulative incidence of ARE was estimated using competing risks methodology; univariate and multivariable regression models were generated to estimate the subdistribution hazard (sHR) of ARE.

Results: Two-year cumulative incidence of ARE was 4.5% and 2.1% in patients treated with and without ICI, respectively (Gray's P = .004). Of the 52 metastases exhibiting ARE during the follow-up period, ARE severity by Common Terminology Criteria for Adverse Events v4 was grade 1 in 14 patients, grade 2 in 15, grade 3 in 9, and grade 4 in 14. There were no grade 5 events. Factors associated with an increased sHR of ARE on univariate analysis included ICI, metastasis volume, SRS dose, prescription isodose line, cavity-directed SRS, and V12. Multivariable analysis revealed prescription isodose line (sHR 0.95, P < .01) and ICI (sHR 2.58, P < .01) as significant predictors of ARE. Increasing V12 was associated with a rapidly increasing risk of adverse radiation effect in patients who received ICI.

Conclusions: Our findings suggest that patients receiving ICI have an increased risk of ARE after radiosurgery for brain metastases, with large metastases being at particularly high risk.
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http://dx.doi.org/10.1016/j.ijrobp.2020.06.057DOI Listing
September 2020

Hippocampal CA1 and CA3 neural recording in the human brain: validation of depth electrode placement through high-resolution imaging and electrophysiology.

Neurosurg Focus 2020 07;49(1):E5

2Neurology.

Objective: Intracranial human brain recordings typically utilize recording systems that do not distinguish individual neuron action potentials. In such cases, individual neurons are not identified by location within functional circuits. In this paper, verified localization of singly recorded hippocampal neurons within the CA3 and CA1 cell fields is demonstrated.

Methods: Macro-micro depth electrodes were implanted in 23 human patients undergoing invasive monitoring for identification of epileptic seizure foci. Individual neurons were isolated and identified via extracellular action potential waveforms recorded via macro-micro depth electrodes localized within the hippocampus. A morphometric survey was performed using 3T MRI scans of hippocampi from the 23 implanted patients, as well as 46 normal (i.e., nonepileptic) patients and 26 patients with a history of epilepsy but no history of depth electrode placement, which provided average dimensions of the hippocampus along typical implantation tracks. Localization within CA3 and CA1 cell fields was tentatively assigned on the basis of recording electrode site, stereotactic positioning of the depth electrode in comparison with the morphometric survey, and postsurgical MRI. Cells were selected as candidate CA3 and CA1 principal neurons on the basis of waveform and firing rate characteristics and confirmed within the CA3-to-CA1 neural projection pathways via measures of functional connectivity.

Results: Cross-correlation analysis confirmed that nearly 80% of putative CA3-to-CA1 cell pairs exhibited positive correlations compatible with feed-forward connection between the cells, while only 2.6% exhibited feedback (inverse) connectivity. Even though synchronous and long-latency correlations were excluded, feed-forward correlation between CA3-CA1 pairs was identified in 1071 (26%) of 4070 total pairs, which favorably compares to reports of 20%-25% feed-forward CA3-CA1 correlation noted in published animal studies.

Conclusions: This study demonstrates the ability to record neurons in vivo from specified regions and subfields of the human brain. As brain-machine interface and neural prosthetic research continues to expand, it is necessary to be able to identify recording and stimulation sites within neural circuits of interest.
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http://dx.doi.org/10.3171/2020.4.FOCUS20164DOI Listing
July 2020

PET Imaging of [C]MPC-6827, a Microtubule-Based Radiotracer in Non-Human Primate Brains.

Molecules 2020 May 13;25(10). Epub 2020 May 13.

Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

Dysregulation of microtubules is commonly associated with several psychiatric and neurological disorders, including addiction and Alzheimer's disease. Imaging of microtubules in vivo using positron emission tomography (PET) could provide valuable information on their role in the development of disease pathogenesis and aid in improving therapeutic regimens. We developed [C]MPC-6827, the first brain-penetrating PET radiotracer to image microtubules in vivo in the mouse brain. The aim of the present study was to assess the reproducibility of [C]MPC-6827 PET imaging in non-human primate brains. Two dynamic 0-120 min PET/CT imaging scans were performed in each of four healthy male cynomolgus monkeys approximately one week apart. Time activity curves (TACs) and standard uptake values (SUVs) were determined for whole brains and specific regions of the brains and compared between the "test" and "retest" data. [C]MPC-6827 showed excellent brain uptake with good pharmacokinetics in non-human primate brains, with significant correlation between the test and retest scan data ( = 0.77, = 0.023). These initial evaluations demonstrate the high translational potential of [C]MPC-6827 to image microtubules in the brain in vivo in monkey models of neurological and psychiatric diseases.
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http://dx.doi.org/10.3390/molecules25102289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287733PMC
May 2020

Rhesus Macaque Brain Developmental Trajectory: A Longitudinal Analysis Using Tensor-Based Structural Morphometry and Diffusion Tensor Imaging.

Cereb Cortex 2020 06;30(8):4325-4335

Radiology Informatics and Image Processing Laboratory (RIIPL), Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

The typical developmental trajectory of brain structure among nonhuman primates (NHPs) remains poorly understood. In this study, we characterized the normative trajectory of developmental change among a cohort of rhesus monkeys (n = 28), ranging in age from 2 to 22 months, using structural MRI datasets that were longitudinally acquired every 3-4 months. We hypothesized that NHP-specific transient intracranial volume decreases reported during late infancy would be part of the typical developmental process, which is driven by volumetric contraction of gray matter in primary functional areas. To this end, we performed multiscale analyses from the whole brain to voxel level, characterizing regional heterogeneity, hemispheric asymmetry, and sexual dimorphism in developmental patterns. The longitudinal trajectory of brain development was explained by three different regional volumetric growth patterns (exponentially decreasing, undulating, and linearly increasing), which resulted in developmental brain volume curves with transient brain volumetric decreases. White matter (WM) fractional anisotropy increased with age, corresponding to WM volume increases, while mean diffusivity (MD) showed biphasic patterns. The longitudinal trajectory of brain development in young rhesus monkeys follows typical maturation patterns seen in humans, but regional volumetric and MD changes are more dynamic in rhesus monkeys compared with humans, with marked decreases followed by "rebound-like" increases.
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http://dx.doi.org/10.1093/cercor/bhaa015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325797PMC
June 2020

Impact of brain metastasis velocity on neurologic death for brain metastasis patients experiencing distant brain failure after initial stereotactic radiosurgery.

J Neurooncol 2020 Jan 1;146(2):285-292. Epub 2020 Jan 1.

Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.

Purpose: Patients with high rates of developing new brain metastases have an increased likelihood of dying of neurologic death. It is unclear, however, whether this risk is affected by treatment choice following failure of primary stereotactic radiosurgery (SRS).

Methods: From July 2000 to March 2017, 440 patients with brain metastasis were treated with SRS and progressed to have a distant brain failure (DBF). Eighty-seven patients were treated within the immunotherapy era. Brain metastasis velocity (BMV) was calculated for each patient. In general, the institutional philosophy for use of salvage SRS vs whole brain radiotherapy (WBRT) was to postpone the use of WBRT for as long as possible and to treat with salvage SRS when feasible. No further treatment was reserved for patients with poor life expectancy and who were not expected to benefit from salvage treatment.

Results: Two hundred and eighty-five patients were treated with repeat SRS, 91 patients were treated with salvage WBRT, and 64 patients received no salvage radiation therapy. One-year cumulative incidence of neurologic death after salvage SRS vs WBRT was 15% vs 23% for the low- (p = 0.06), 30% vs 37% for the intermediate- (p < 0.01), and 31% vs 48% (p < 0.01) for the high-BMV group. Salvage WBRT was associated with increased incidence of neurologic death on multivariate analysis (HR 1.64, 95% CI 1.13-2.39, p = 0.01) when compared to repeat SRS. One-year cumulative incidence of neurologic death for patients treated within the immunotherapy era was 9%, 38%, and 38% for low-, intermediate-, and high-BMV groups, respectively (p = 0.01).

Conclusion: Intermediate and high risk BMV groups are predictive of neurologic death. The association between BMV and neurologic death remains strong for patients treated within the immunotherapy era.
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http://dx.doi.org/10.1007/s11060-019-03368-9DOI Listing
January 2020

Traumatic Brain Injury: Imaging Patterns and Complications.

Radiographics 2019 10;39(6):1571-1595

From the Department of Radiology, Weill Cornell Medicine/New York-Presbyterian Hospital, 525 E 68th St, Starr 630C, New York, NY 10075 (A.D.S., S.N.N., A.J.T.); and Department of Radiology, Wake Forest School of Medicine, Winston-Salem, N.C. (C.T.W.).

While the diagnosis of traumatic brain injury (TBI) is a clinical decision, neuroimaging remains vital for guiding management on the basis of identification of intracranial pathologic conditions. CT is the mainstay of imaging of acute TBI for both initial triage and follow-up, as it is fast and accurate in detecting both primary and secondary injuries that require neurosurgical intervention. MRI is more sensitive for the detection of certain intracranial injuries (eg, axonal injuries) and blood products 24-48 hours after injury, but it has limitations (eg, speed, accessibility, sensitivity to motion, and cost). The evidence primarily supports the use of MRI when CT findings are normal and there are persistent unexplained neurologic findings or at subacute and chronic periods. Radiologists should understand the role and optimal imaging modality to use, in addition to patterns of primary brain injury and their influence on the risk of developing secondary brain injuries related to herniation. RSNA, 2019 See discussion on this article by Mathur and Nicolaou.
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http://dx.doi.org/10.1148/rg.2019190076DOI Listing
October 2019

The 2019 Monograph Issue: Emergency Neuroradiology.

Radiographics 2019 10;39(6):1569-1570

From the Department of Radiology, Wake Forest University School of Medicine, Winston-Salem, NC (C.T.W.); Division of Emergency Radiology, Department of Radiology, Massachusetts General Hospital, Boston, Mass (M.H.L); and Department of Radiology, University of Cincinnati Medical Center, 234 Goodman St, Cincinnati, OH 45267-0525 (A.S.V.).

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http://dx.doi.org/10.1148/rg.2019194010DOI Listing
October 2019

Physical Performance Measures Correlate with Head Impact Exposure in Youth Football.

Med Sci Sports Exerc 2020 02;52(2):449-456

Department of Radiology, University of Texas Southwestern, Dallas, TX.

Purpose: Head impact exposure (HIE) (i.e., magnitude and frequency of impacts) can vary considerably among individuals within a single football team. To better understand individual-specific factors that may explain variation in head impact biomechanics, this study aimed to evaluate the relationship between physical performance measures and HIE metrics in youth football players.

Methods: Head impact data were collected from youth football players using the Head Impact Telemetry System. Head impact exposure was quantified in terms of impact frequency, linear and rotational head acceleration, and risk-weighted cumulative exposure metrics (RWELinear, RWERotational, and RWECP). Study participants completed four physical performance tests: vertical jump, shuttle run, three-cone, and 40-yard sprint. The relationships between performance measures, and HIE metrics were evaluated using linear regression analyses.

Results: A total of 51 youth football athletes (ages, 9-13 yr) completed performance testing and received combined 13,770 head impacts measured with the Head Impact Telemetry System for a full season. All performance measures were significantly correlated with total number of impacts in a season, RWELinear-Season, and all RWE-Game metrics. The strongest relationships were between 40-yard sprint speed and all RWE-Game metrics (all P ≤ 0.0001 and partial R > 0.3). The only significant relationships among HIE metrics in practice were between shuttle run speed and total practice impacts and RWELinear-Practices, 40 yard sprint speed and total number of practice impacts, and three-cone speed and 95th percentile number of impacts/practice.

Conclusions: Generally, higher vertical jump height and faster times in speed and agility drills were associated with higher HIE, especially in games. Physical performance explained less variation in HIE in practices, where drills and other factors, such as coaching style, may have a larger influence on HIE.
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http://dx.doi.org/10.1249/MSS.0000000000002144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962548PMC
February 2020

Reward, Control & Decision-Making in Cannabis Use Disorder: Insights from Functional MRI.

Br J Radiol 2019 Sep 9;92(1101):20190165. Epub 2019 Aug 9.

1Department of Radiology, Wake Forest School of Medicine, Section of Neuroradiology, Winston-Salem, North Carolina, United States.

The recreational consumption of cannabis has increased significantly across the world with an estimated 180 million people currently using. In the United States, 4.1 million are currently diagnosed with cannabis use disorder. Cannabis dependence and abuse was combined into a single entity as a behavioral disorder with a problematic pattern of cannabis use and termed cannabis use disorder by the Diagnostic and Statistical Manual of Mental Disorders. Chronic use of cannabis has been linked with region-specific effects across the brain mediating reward processing, cognitive control and decision-making that are central to understanding addictive behaviors. This review presents a snapshot of the current literature assessing the effects of chronic cannabis use on human brain function via functional MRI. Studies employing various paradigms and contrasting cognitive activation amongst cannabis users and non-users were incorporated. The effects of trans-del-ta-9-tetrahydrocannabinol (Δ9-THC) in marijuana and other preparations of cannabis are mediated by the endocannabinoid system, which is also briefly introduced.Much variation exists in the current literature regarding the functional changes associated with chronic cannabis use. One possible explanation for this variation is the heterogeneity in study designs, with little implementation of standardized diagnostic criteria when selecting chronic users, distinct time points of participant assessment, differing cognitive paradigms and imaging protocols. As such, there is an urgent requirement for future investigations that further characterize functional changes associated with chronic cannabis use.
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http://dx.doi.org/10.1259/bjr.20190165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732906PMC
September 2019

Revising rapid-onset dystonia-parkinsonism: Broadening indications for ATP1A3 testing.

Mov Disord 2019 10 30;34(10):1528-1536. Epub 2019 Jul 30.

Department of Neurology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

Background And Objectives: Rapid-onset dystonia-parkinsonism (RDP) is caused by mutations in the ATP1A3 gene, which codes for the α-3 subunit of the Na /K ATPase. It has been characterized by rapid-onset bulbar dysfunction, limb dystonia, bradykinesia, and a rostrocaudal spatial gradient of expression, usually after a physiologic trigger. We reexamined whether these features were in fact characteristic.

Methods: We characterized phenotypic variation within a cohort of 50 ATP1A3 mutation-positive individuals (carriers) and 44 mutation-negative family members (noncarriers). Potential participants were gathered through referral for clinical suspicion of RDP or alternating hemiplegia of childhood. Inclusion criteria were having a ATP1A3 mutation or being a family member of such an individual.

Results: We found RDP is underdiagnosed if only "characteristic" patients are tested. Rapid onset and bulbar predominance were not universally present in carriers. Among those with at least mild symptoms of dystonia, rostrocaudal severity gradient was rare (7%). Symptoms began focally but progressed to be generalized (51%) or multifocal (49%). Arm (41%) onset was most common. Arms and voice were typically most severely affected (48% and 44%, respectively). Triggers preceded onset in 77% of the participants. Rapid onset, dystonia, parkinsonism, bulbar symptoms, headaches, seizures, frontal impairment, and a history of mood disorder and a history of psychosis were more common in carriers. Approximately half of the proband mutations occurred de novo (56%).

Conclusions: Our findings suggest that patients should not be excluded from ATP1A3 testing because of slow onset, limb onset, absent family history, or onset in middle adulthood. RDP should be strongly considered in the differential for any bulbar dystonia. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879786PMC
October 2019

Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy.

Sci Transl Med 2019 06;11(496)

Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.

Endogenous costimulatory molecules on T cells such as 4-1BB (CD137) can be leveraged for cancer immunotherapy. Systemic administration of agonistic anti-4-1BB antibodies, although effective preclinically, has not advanced to phase 3 trials because they have been hampered by both dependency on Fcγ receptor-mediated hyperclustering and hepatotoxicity. To overcome these issues, we engineered proteins simultaneously targeting 4-1BB and a tumor stroma or tumor antigen: FAP-4-1BBL (RG7826) and CD19-4-1BBL. In the presence of a T cell receptor signal, they provide potent T cell costimulation strictly dependent on tumor antigen-mediated hyperclustering without systemic activation by FcγR binding. We could show targeting of FAP-4-1BBL to FAP-expressing tumor stroma and lymph nodes in a colorectal cancer-bearing rhesus monkey. Combination of FAP-4-1BBL with tumor antigen-targeted T cell bispecific (TCB) molecules in human tumor samples led to increased IFN-γ and granzyme B secretion. Further, combination of FAP- or CD19-4-1BBL with CEA-TCB (RG7802) or CD20-TCB (RG6026), respectively, resulted in tumor remission in mouse models, accompanied by intratumoral accumulation of activated effector CD8 T cells. FAP- and CD19-4-1BBL thus represent an off-the-shelf combination immunotherapy without requiring genetic modification of effector cells for the treatment of solid and hematological malignancies.
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http://dx.doi.org/10.1126/scitranslmed.aav5989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181714PMC
June 2019

Ca and CACNA1H mediate targeted suppression of breast cancer brain metastasis by AM RF EMF.

EBioMedicine 2019 Jun 23;44:194-208. Epub 2019 May 23.

Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States of America. Electronic address:

Background: Brain metastases are a major cause of death in patients with metastatic breast cancer. While surgical resection and radiation therapy are effective treatment modalities, the majority of patients will succumb from disease progression. We have developed a novel therapy for brain metastases that delivers athermal radiofrequency electromagnetic fields that are amplitude-modulated at breast cancer specific frequencies (BCF).

Methods: 27.12 MHz amplitude-modulated BCF were administered to a patient with a breast cancer brain metastasis by placing a spoon-shaped antenna on the anterior part of the tongue for three one-hour treatments every day. In preclinical models, a BCF dose, equivalent to that delivered to the patient's brain, was administered to animals implanted with either brain metastasis patient derived xenografts (PDXs) or brain-tropic cell lines. We also examined the efficacy of combining radiation therapy with BCF treatment. Additionally, the mechanistic underpinnings associated with cancer inhibition was identified using an agnostic approach.

Findings: Animal studies demonstrated a significant decrease in growth and metastases of brain-tropic cell lines. Moreover, BCF treatment of PDXs established from patients with brain metastases showed strong suppression of their growth ability. Importantly, BCF treatment led to significant and durable regression of brain metastasis of a patient with triple negative breast cancer. The tumour inhibitory effect was mediated by Ca influx in cancer cells through CACNA1H T-type voltage-gated calcium channels, which, acting as the cellular antenna for BCF, activated CAMKII/p38 MAPK signalling and inhibited cancer stem cells through suppression of β-catenin/HMGA2 signalling. Furthermore, BCF treatment downregulated exosomal miR-1246 level, which in turn decreased angiogenesis in brain environment. Therefore, targeted growth inhibition of breast cancer metastases was achieved through CACNA1H.

Interpretation: We demonstrate that BCF, as a single agent or in combination with radiation, is a novel treatment approach to the treatment of brain metastases. This paradigm shifting modality warrants further clinical trials for this unmet medical need.
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http://dx.doi.org/10.1016/j.ebiom.2019.05.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604768PMC
June 2019

Evaluation of head impact exposure measured from youth football game plays.

J Neurosurg Pediatr 2019 May 10;24(2):190-199. Epub 2019 May 10.

1Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Winston-Salem.

Objective: There is a growing body of literature informing efforts to improve the safety of football; however, research relating on-field activity to head impacts in youth football is limited. Therefore, the objective of this study was to compare head impact exposure (HIE) measured in game plays among 3 youth football teams.

Methods: Head impact and video data were collected from athletes (ages 10-13 years) participating on 3 youth football teams. Video analysis was performed to verify head impacts and assign each to a specific play type. Each play was categorized as a down, punt, kickoff, field goal, or false start. Kickoffs and punts were classified as special teams. Downs were classified as running, passing, or other. HIE was quantified by play type in terms of mean, median, and 95th percentile linear and rotational acceleration. Mixed-effects models were used to assess differences in acceleration among play types. Contact occurring on special teams plays was evaluated using a standardized video abstraction form.

Results: A total of 3003 head impacts over 27.5 games were analyzed and paired with detailed video coding of plays. Most head impacts were attributed to running (79.6%), followed by passing (14.0%), and special teams (6.4%) plays. The 95th percentile linear acceleration measured during each play type was 52.6g, 50.7g, and 65.5g, respectively. Special teams had significantly greater mean linear acceleration than running and passing plays (both p = 0.03). The most common kick result on special teams was a deep kick, of which 85% were attempted to be returned. No special teams plays resulted in a touchback, and one resulted in a fair catch. One-third of all special teams plays and 92% of all nonreturned kicks resulted in athletes diving toward the ball.

Conclusions: The results demonstrate a trend toward higher head impact magnitudes on special teams than for running and passing plays, but a greater number of impacts were measured during running plays. Deep kicks were most common on special teams, and many returned and nonreturned kicks resulted in athletes diving toward the ball. These results support policy changes to youth special teams plays, including modifying the yard line the ball is kicked from and coaching proper return technique. Further investigation into biomechanical exposure measured during game impact scenarios is needed to inform policy relevant to the youth level.
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http://dx.doi.org/10.3171/2019.2.PEDS18558DOI Listing
May 2019

Association of Head Injury with Brain Amyloid Deposition: The ARIC-PET Study.

J Neurotrauma 2019 09 23;36(17):2549-2557. Epub 2019 May 23.

Department of Neurology, Johns Hopkins University, Baltimore, Maryland.

Our objective was to examine associations of head injury with total and regional brain amyloid deposition. We performed cross-sectional analyses of 329 non-demented participants (81 with prior head injury) in the Atherosclerosis Risk in Communities-Positron Emission Tomography (ARIC-PET) Study who underwent florbetapir PET imaging in 2012-2014. A history of head injury was defined by self-report or emergency department/hospitalization International Classification of Diseases, Ninth Revision codes. Generalized linear regression models adjusted for demographic, socioeconomic, and dementia/cardiovascular risk factors were used to estimate prevalence ratios (PRs; 95% confidence intervals [CIs]) for elevated (> 1.2) global and regional standard uptake value ratios (SUVRs). Mean age of participants was 76 years, 57% were women, and 43% were black. Head injury was associated with increased prevalence of elevated SUVR >1.2 globally (PR: 1.31; 95% CI: 1.19-1.57), as well as in the orbitofrontal cortex (PR: 1.23); (95% CI: 1.04-1.46), prefrontal cortex (PR: 1.18; 95% CI: 1.00-1.39), superior frontal cortex (PR: 1.24; 95% CI: 1.05-1.48), and posterior cingulate (PR: 1.26; 95% CI: 1.04-1.52). There also was evidence for a dose-response relationship, whereby a history of ≥1 head injury was associated with elevated SUVR >1.2 in the prefrontal cortex and superior frontal cortex compared with persons with a history of one head injury (all,  < 0.05). In conclusion, head injury was associated with increased amyloid deposition globally and in the frontal cortex and posterior cingulate, with suggestion of a dose-response association of head injuries with beta-amyloid deposition. Further work is needed to determine if increased amyloid deposition contributes to dementia in this population.
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http://dx.doi.org/10.1089/neu.2018.6213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909743PMC
September 2019
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