Anthony Chesebro

Anthony Chesebro

MS4 in MSTP (PhD in Biomedical Engineering)

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Structural Brain Changes in Pre-Clinical FTD MAPT Mutation Carriers

Published in Journal of Alzheimer's Disease, 2020

Frontotemporal dementia (FTD) is the second most common cause of early-onset neurodegenerative dementia. Several studies have focused on early imaging changes in FTD patients, but once subjects meet full criteria for FTD diagnosis, structural changes are generally widespread. This study aims to determine the earliest structural brain changes in asymptomatic MAPT mutation carriers. This is a cross-sectional multicenter study comparing global and regional brain volume and white matter integrity in MAPT mutation preclinical carriers and controls from multiple generations of six families with five MAPT mutations. All participants underwent a medical examination, neuropsychological tests, genetic analysis, and a magnetic resonance scan. Volumes of five cortical and subcortical areas were strongly correlated with mutation status: temporal lobe (left amygdala, left temporal pole), cingulate cortex (left rostral anterior cingulate gyrus, right posterior cingulate), and the lingual gyrus in the occipital lobe. No significant differences in whole brain volume, white matter hyperintensities volume, or white matter integrity using DTI analysis were found. Temporal lobe, cingulate cortex and the lingual gyrus appear to be early targets of the disease and may serve as biomarkers for FTD prior to overt symptom onset.

Recommended citation: Domínguez-Vivero, C, Wu, L, Lee, S, Manoochehri, M, Cines, S, Brickman, AM, Rizvi, B, Chesebro, AG, Gazes, Y, Fallon, E, Lynch, T, Heidebrink, JL, Paulson, H, Goldman, JS, Huey, E, Cosentino, S. Structural Brain Changes in Pre-Clinical FTD MAPT Mutation Carriers. J Alzheimers Dis. 2020;75(2):595-606.
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White matter hyperintensities mediate the association of nocturnal blood pressure with cognition

Published in Neurology, 2020

We tested the hypotheses that hypertension and nocturnal blood pressure are related to white matter hyperintensity (WMH) volume, an MRI marker of small vessel cerebrovascular disease, and that WMH burden statistically mediates the association of hypertension and dipping status with memory functioning. Participants from the community-based Maracaibo Aging Study received ambulatory 24-hour blood pressure monitoring, structural MRI, and neuropsychological assessment. Four hundred thirty-five participants (mean age 59 ± 13 years, 71% women) were included. Ambulatory blood pressure was used to define hypertension and dipping status (dipper, nondipper, and reverse dipper). The majority (59%) were hypertensive. Reverse dipping in the presence of hypertension was associated with particularly elevated periventricular WMH volume and with lowered memory scores. Periventricular WMH volume mediated the effect of dipping status and hypertension on memory (β = -4.1, 95% CI -8.7 to -0.2). Reverse dipping in the presence of hypertension is associated with small vessel cerebrovascular disease, which, in turn, mediates memory functioning, pointing toward reverse dipping as a marker of poor nocturnal blood pressure control with potentially pernicious effects on cerebrovascular health and cognition.

Recommended citation: Chesebro, AG, Melgarejo, JD, Leendertz, R, Igwe, KC, Lao, PJ, Laing, KK, Rizvi, B, Budge, M, Meier, IB, Calmon, G, Lee, JH, Maestre, GE, Brickman, AM. White matter hyperintensities mediate the association of nocturnal blood pressure with cognition. Neurology. 2020 Apr 28;94(17):e1803-e1810.
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Cerebrovascular disease promotes tau pathology in Alzheimer’s disease

Published in Brain Communications, 2020

Small vessel cerebrovascular disease, visualized as white matter hyperintensities on T2-weighted magnetic resonance imaging, contributes to the clinical presentation of Alzheimer’s disease. However, the extent to which cerebrovascular disease represents an independent pathognomonic feature of Alzheimer’s disease or directly promotes Alzheimer’s pathology is unclear. The purpose of this study was to examine the association between white matter hyperintensities and plasma levels of tau and to determine if white matter hyperintensities and tau levels interact to predict Alzheimer’s disease diagnosis. Three hundred ninety-one participants from the Alzheimer’s Disease Neuroimaging Initiative were included. Increased white matter hyperintensity volume was associated with higher plasma tau concentration, particularly among those diagnosed clinically with Alzheimer’s disease. Presence of brain amyloid and the interaction between plasma tau and white matter hyperintensity volume distinguished Alzheimer’s disease and mild cognitive impairment participants from controls with 77.6% and 63.3% accuracy, respectively. In a transient middle cerebral artery occlusion mouse model, aged mice that received transient middle cerebral artery occlusion had increased plasma and cerebrospinal fluid tau concentrations, induced myelin loss, and hyperphosphorylated tau pathology in the ipsilateral hippocampus and cerebral hemisphere. These findings demonstrate a relationship between cerebrovascular disease and tau levels, suggesting that hypoperfusive injury promotes tau pathology.

Recommended citation: Laing, KK, Simoes, S, Baena-Caldas, GP, Lao, PJ, Kothiya, M, Igwe, KC, Chesebro, AG, Houck, AL, Pedraza, L, Hernández, AI, Li, J, Zimmerman, ME, Luchsinger, JA, Barone, FC, Moreno, H, Brickman, AM; Alzheimer's Disease Neuroimaging Initiative. Cerebrovascular disease promotes tau pathology in Alzheimer's disease. Brain Commun. 2020 Aug 19;2(2):fcaa132.
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APOE ε4 and resting-state functional connectivity in racially/ethnically diverse older adults

Published in Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 2020

Numerous neuroimaging studies demonstrated an association between the apolipoprotein E (APOE) ε4 allele and resting-state functional connectivity (rsFC) of regions within the default mode network (DMN), both in healthy populations and patients with AD. It remains unclear whether the APOE ε4 allele differentially affects the brain functional network architecture across race/ethnicity. We investigated rsFC within DMN subsystems in 170 APOE ε4 carriers compared to 387 APOE ε4 non-carriers across three major racial/ethnic groups, including non-Hispanic Whites (n = 166), non-Hispanic Blacks (n = 185), and Hispanics (n = 206) from the Washington Heights-Inwood Columbia Aging Project. Compared to APOE ε4 non-carriers, APOE ε4 carriers had lower rsFC in temporal DMN, but only in non-Hispanic Whites. Non-Hispanic Black and Hispanic APOE ε4 carriers had slightly higher or similar rsFC compared with non-Hispanic White APOE ε4 non-carriers. These findings suggest that APOE ε4 modulates DMN rsFC differently in non-Hispanic Whites compared with non-Hispanic Blacks and Hispanics.

Recommended citation: Turney, IC, Chesebro, AG, Rentería, MA, Lao, PJ, Beato, JM, Schupf, N, Mayeux, R, Manly, JJ, Brickman, AM. APOE ε4 and resting-state functional connectivity in racially/ethnically diverse older adults. Alzheimers Dement (Amst). 2020 Sep 22;12(1):e12094.
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Parental History of Dementia Is Associated with Increased Small Vessel Cerebrovascular Disease

Published in The Journals of Gerontology: Series A, 2020

Small vessel cerebrovascular dysfunction that manifests on magnetic resonance imaging (MRI) as white matter hyperintensities (WMH) is linked to increased risk and progression of Alzheimer’s disease (AD), but there is considerable debate about whether it represents a core feature of the disease. Parental history of dementia is a risk factor for AD, suggesting a strong heritable component; the examination of the extent to which parental history of dementia is associated with cerebrovascular disease could provide insight into the aggregation of AD and cerebrovascular disease. This study included 481 community-dwelling older adults with available MRI scans. Those with parental history had greater total WMH volume than those without (F = 4.17, p = .042). Results were strongest for those with maternal versus paternal history and among Hispanic and non-Hispanic White participants. Those with reported sibling history of dementia did not differ from those without. Older adults with parental, particularly maternal, history of dementia have increased WMH, highlighting the possibility that cerebrovascular changes are a core feature of AD.

Recommended citation: Stamm, BC, Lao, PJ, Rizvi, B, Colon, J, Igwe, K, Chesebro, AG, Maas, B, Schupf, N, Mayeux, R, Manly, JJ, Brickman, AM. Parental History of Dementia Is Associated with Increased Small Vessel Cerebrovascular Disease. J Gerontol A Biol Sci Med Sci. 2020 Oct 15;75(11):2156-2161.
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Assessment of leisure time physical activity and brain health in a multiethnic cohort of older adults

Published in JAMA Network Open, 2020

Results from longitudinal studies suggest that regular leisure time physical activity (LTPA) is associated with reduced risk of dementia or Alzheimer disease. This cross-sectional study included 1443 older (≥65 years) adults without dementia from the Washington/Hamilton Heights-Inwood Columbia Aging Project. LTPA was calculated as metabolic equivalent of energy expenditure. Compared with the LTPA of nonactive older adults, those with the most LTPA had larger total brain volume (β 13.17 cm3; P = .003) and greater cortical thickness (β 0.016 mm; P = .05). The effect size comparing the highest LTPA level with the nonactive group was equivalent to approximately 3 to 4 years of aging. A dose-response association was found and even the lowest LTPA level had benefits compared with the nonactive group. Meeting Physical Activity Guidelines for Americans and light-intensity LTPA were also associated with larger brain measures. The association between LTPA and total brain volume was moderated by race/ethnicity, sex, and APOE status, but generally existed in all subgroups. In this study, more physical activity was associated with larger brain volume in older adults.

Recommended citation: Gu, Y, Beato, JM, Amarante, E, Chesebro, AG, Manly, JJ, Schupf, N, Mayeux, RP, Brickman, AM. Assessment of leisure time physical activity and brain health in a multiethnic cohort of older adults. JAMA Netw Open. 2020 Nov 2;3(11):e2026506.
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Education differentially contributes to cognitive reserve across racial/ethnic groups

Published in Alzheimer's & Dementia, 2021

We examined whether educational attainment differentially contributes to cognitive reserve (CR) across race/ethnicity. A total of 1553 non-Hispanic Whites, non-Hispanic Blacks, and Hispanics in the Washington Heights-Inwood Columbia Aging Project (WHICAP) completed structural magnetic resonance imaging. Mixture growth curve modeling was used to examine whether the effect of brain integrity indicators (hippocampal volume, cortical thickness, and white matter hyperintensity [WMH] volumes) on memory and language trajectories was modified by education across racial/ethnic groups. Higher educational attainment attenuated the negative impact of WMH burden on memory and language decline, as well as the impact of cortical thinning on level of language performance for Whites, but not for Blacks or Hispanics. Educational attainment does not contribute to CR similarly across racial/ethnic groups.

Recommended citation: Avila, JF, Rentería, MA, Jones, RN, Vonk, JMJ, Turney, I, Sol, K, Seblova, D, Arias, F, Hill-Jarrett, T, Levy, SA, Meyer, O, Racine, AM, Tom, SE, Melrose, RJ, Deters, K, Medina, LD, Carrión, CI, Díaz-Santos, M, Byrd, DR, Chesebro, AG, Colon, J, Igwe, KC, Maas, B, Brickman, AM, Schupf, N, Mayeux, R, Manly, JJ. Education differentially contributes to cognitive reserve across racial/ethnic groups. Alzheimers Dement. 2021 Jan;17(1):70-80.
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Automated detection of cerebral microbleeds on T2*-weighted MRI

Published in Scientific Reports, 2021

Cerebral microbleeds, observed as small, spherical hypointense regions on gradient echo (GRE) or susceptibility weighted (SWI) magnetic resonance imaging (MRI) sequences, reflect small hemorrhagic infarcts, and are associated with conditions such as vascular dementia, small vessel disease, cerebral amyloid angiopathy, and Alzheimer’s disease. The current gold standard for detecting and rating cerebral microbleeds in a research context is visual inspection by trained raters, a process that is both time consuming and subject to poor reliability. We present here a novel method to automate microbleed detection on GRE and SWI images. We demonstrate in a community-based cohort of older adults that the method is highly sensitive (greater than 92% of all microbleeds accurately detected) across both modalities, with reasonable precision (fewer than 20 and 10 false positives per scan on GRE and SWI, respectively). We also demonstrate that the algorithm can be used to identify microbleeds over longitudinal scans with a higher level of sensitivity than visual ratings (50% of longitudinal microbleeds correctly labeled by the algorithm, while manual ratings was 30% or lower). Further, the algorithm identifies the anatomical localization of microbleeds based on brain atlases, and greatly reduces time spent completing visual ratings (43% reduction in visual rating time).

Recommended citation: Chesebro, AG, Amarante, E, Lao, PJ, Meier, IB, Mayeux, R, Brickman, AM. Automated detection of cerebral microbleeds on T2*-weighted MRI. Sci Rep. 2021 Feb 17;11(1):4004.
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Association of regional white matter hyperintensities with longitudinal Alzheimer-like pattern of neurodegeneration in older adults

Published in JAMA Network Open, 2021

Small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH), is associated with cognitive decline and risk of clinical Alzheimer disease. One way in which small vessel cerebrovascular disease could contribute to AD is through the promotion of neurodegeneration. In 303 participants (mean age 73.16 years, 60% women) from the Washington Heights-Inwood Columbia Aging Project who underwent two 3T MRI scans a mean of 4 years apart, baseline WMH volumes were associated with cortical thinning in medial temporal and frontal/parietal regions. Specifically, total WMH volume was associated with cortical thinning in the right caudal middle frontal cortex and paracentral cortex, whereas parietal WMH volume was associated with atrophy in the left entorhinal cortex and right rostral middle frontal, paracentral, and pars triangularis cortices. Thinning of the right caudal middle frontal and left entorhinal cortices was related to lower scores on a memory test administered closest to the second MRI visit. The association of total WMH with thinning in frontal and paracentral cortices was greater in non-Hispanic Black participants compared with White participants. In this study, small vessel cerebrovascular disease was associated with subsequent cortical atrophy in regions that overlap with typical AD neurodegeneration patterns, particularly among non-Hispanic Black older adults, suggesting cerebrovascular disease may affect risk and progression of AD by promoting neurodegeneration and subsequent memory decline.

Recommended citation: Rizvi, B, Lao, PJ, Chesebro, AG, Dworkin, JD, Amarante, E, Beato, JM, Gutierrez, J, Zahodne, LB, Schupf, N, Manly, JJ, Mayeux, R, Brickman, AM. Association of regional white matter hyperintensities with longitudinal Alzheimer-like pattern of neurodegeneration in older adults. JAMA Netw Open. 2021 Oct 1;4(10):e2125166.
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Automatic quantification of white matter hyperintensities on T2-weighted fluid attenuated inversion recovery magnetic resonance imaging

Published in Magnetic Resonance Imaging, 2022

White matter hyperintensities (WMH) are areas of increased signal visualized on T2-weighted fluid attenuated inversion recovery (FLAIR) brain magnetic resonance imaging (MRI) sequences. They are typically attributed to small vessel cerebrovascular disease in the context of aging. Among older adults, WMH are associated with risk of cognitive decline and dementia, stroke, and various other health outcomes. There has been increasing interest in incorporating quantitative WMH measurement as outcomes in clinical trials, observational research, and clinical settings. Here, we present a novel, fully automated, unsupervised detection algorithm for WMH segmentation and quantification. The algorithm uses a robust preprocessing pipeline, including brain extraction and a sample-specific mask that incorporates spatial information for automatic false positive reduction, and a half Gaussian mixture model (HGMM). The method was evaluated in 24 participants with varying degrees of WMH from a community-based study of aging and dementia with dice coefficient, sensitivity, specificity, correlation, and bias relative to the ground truth manual segmentation approach. Results were compared with those derived from commonly used available WMH segmentation packages. The HGMM algorithm derived WMH values that had a dice score of 0.87, sensitivity of 0.89, and specificity of 0.99 compared to ground truth, with WMH volumes strongly correlated with ground truth values (r = 0.97).

Recommended citation: Igwe, KC, Lao, PJ, Vorburger, RS, Banerjee, A, Rivera, A, Chesebro, AG, Laing, KK, Manly, JJ, Brickman, AM. Automatic quantification of white matter hyperintensities on T2-weighted fluid attenuated inversion recovery magnetic resonance imaging. Magn Reson Imaging. 2022 Jan; 85:71-79.
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Patterns of tau pathology identified with 18F-MK-6240 PET imaging

Published in Alzheimer's & Dementia, 2022

Positron emission tomography (PET) imaging for neurofibrillary tau allows investigation of the in vivo spatiotemporal progression of Alzheimer disease pathology. We evaluated the suitability of 18F-MK-6240 in a clinical sample and determined the relationships among 18F-MK-6240 binding, age, cognition, and cerebrospinal fluid (CSF)-based AD biomarkers. Participants (n = 101, 72 ± 9 years, 52% women) underwent amyloid PET, tau PET, structural T1-weighted magnetic resonance imaging, and neuropsychological evaluation. Twenty-one participants had lumbar puncture for CSF measurement of amyloid beta (Aβ), tau, and phosphorylated tau (p-tau). 18F-MK-6240 recapitulated Braak staging and correlated with CSF tau and p-tau, normalized to Aβ. 18F-MK-6240 negatively correlated with age across Braak regions in amyloid-positive participants, consistent with greater tau pathology in earlier onset AD. Domain-specific, regional patterns of 18F-MK-6240 binding were associated with reduced memory, executive, and language performance, but only in amyloid-positive participants. 18F-MK-6240 can approximate Braak staging across the AD continuum and provide region-dependent insights into biomarker-based AD models.

Recommended citation: Kreisl, WC, Lao, PJ, Johnson, A, Tomljanovic, Z, Klein, J, Polly, K, Maas, B, Laing, KK, Chesebro, AG, Igwe, K, Razlighi, QR, Honig, LS, Yan, X, Lee, S, Mintz, A, Luchsinger, JA, Stern, Y, Devanand, DP, Brickman, AM. Patterns of tau pathology identified with 18F-MK-6240 PET imaging. Alzheimers Dement. 2022 Feb;18(2):272-282.
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Amyloid, cerebrovascular disease, and neurodegeneration biomarkers are associated with cognitive trajectories in a racially and ethnically diverse, community-based sample

Published in Neurobiology of Aging, 2022

We characterized the additive contribution of cerebrovascular biomarkers to amyloid and neurodegeneration biomarkers (AV(N)) when modeling prospective, longitudinal cognitive trajectories within 3 major racial/ethnic groups. Participants (n = 172; age = 69-96 years; 62% women; 31%/49%/20% Non-Hispanic White/Non-Hispanic Black/Hispanic) from the Washington Heights-Inwood Columbia Aging Project were assessed for amyloid (Florbetaben PET), neurodegeneration (cortical thickness, hippocampal volume), and cerebrovascular disease (white matter hyperintensity (WMH), infarcts). Neuropsychological assessments occurred every 2.3 ± 0.6 years for up to 6 visits (follow-up time: 4.2 ± 3.2 years). Linear mixed-effects models were stratified by race/ethnicity groups. Higher amyloid was associated with faster memory decline in all 3 racial/ethnic groups, but was related to faster cognitive decline beyond memory in minoritized racial/ethnic groups. Higher WMH was associated with faster language, processing speed/executive function, and visuospatial ability decline in Non-Hispanic Black participants, while infarcts were associated with faster processing speed/executive function decline in Non-Hispanic White participants. Complementary information from AD, neurodegenerative, and cerebrovascular biomarkers explain decline in multiple cognitive domains, which may differ within each racial/ethnic group.

Recommended citation: Lao, PJ, Boehme, AK, Morales, C, Laing, KK, Chesebro, AG, Igwe, K, Gutierrez, J, Gu, Y, Stern, Y, Schupf, N, Manly, JJ, Mayeux, R, Brickman, AM. Amyloid, cerebrovascular disease, and neurodegeneration biomarkers are associated with cognitive trajectories in a racially and ethnically diverse, community-based sample. Neurobiol Aging. 2022 Sep;117:83-96.
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First Aid for the USMLE Step 1 2023

Published in McGraw-Hill, 2023

Recommended citation: Associate Author. Le, T, Bhushan, V, Qiu, C, Chalise, A, Kaparaliotis, P (eds.). First Aid for the USMLE Step 1 2023. New York: McGraw-Hill. (2023).
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Serum inflammation markers associated with altered white matter microstructure in an older cohort of people with HIV on antiretroviral treatment

Published in Neurological Sciences, 2023

Many studies have reported reduced brain white matter fractional anisotropy (FA) and increased mean diffusivity (MD) on diffusion tensor imaging (DTI) of people with HIV (PWH). Few, however, have linked individual blood inflammatory markers with white matter tract-specific FA and MD. PWH 50 years old or older from New York, NY, USA, were invited to a cross-sectional study. Demographic data, blood samples, and brain DTI were obtained. Least absolute shrinkage and selection operator (LASSO) regression was used to examine associations between biomarkers and white matter tract-specific FA and MD. All models included age, sex, race, ethnicity, diabetes, hypertension, smoking, and viral load as control variables. Seventy-two cases were analyzed. Mean age was 60 ± 6 years, 47% were women, 21% were Hispanic, and 78% were black. All had asymptomatic HIV infection and were on antiretroviral therapy. Eighty-nine percent had CD4 count >200 cell/mm and 78% were virally suppressed. Vascular endothelial growth factor (VEGF) and macrophage inflammatory proteins (MIP) 1β and 1α were consistently associated with lower FA and higher MD across white matter tracts. Elevated serum VEGF, MIP-1α, and MIP-1β were associated with altered white matter microstructure. These blood biomarkers may help predict HIV-associated white matter damage.

Recommended citation: Spagnolo-Allende, A, Schnall, R, Liu, M, Igwe, KC, Laing, KK, Chesebro, AG, Brickman, AM, Gutierrez, J. Serum inflammation markers associated with altered white matter microstructure in an older cohort of people with HIV on antiretroviral treatment. Neurol Sci. 2023 Jan; 44:2159-2166.
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Ion gradient-driven bifurcations of a multi-scale neuronal model

Published in Chaos, Solitons and Fractals, 2023

Metabolic limitations within the brain frequently arise in the context of aging and disease. As the largest consumers of energy within the brain, ion pumps that maintain the neuronal membrane potential are the most affected when energy supply becomes limited. To characterize the effects of such limitations, we analyze the ion gradients present in a conductance-based (Morris–Lecar) neural mass model. We show the existence and locations of Neimark–Sacker and period-doubling bifurcations in the sodium, calcium, and potassium reversal potentials and demonstrate that these bifurcations form physiologically relevant bounds of ion gradient variability. Within these bounds, we show how depolarization of the gradients causes decreased neural activity. We also show that the depolarization of ion gradients decreases inter-regional coherence, causing a shift in the critical point at which the coupling occurs and thereby inducing loss of synchrony between regions. In this way, we show that the Larter-Breakspear model captures ion gradient variability present at the microscale level and propagates these changes to the macroscale effects such as those observed in human neuroimaging studies.

Recommended citation: Chesebro, AG, Mujica-Parodi, LR, Weistuch, C. Ion gradient-driven bifurcations of a multi-scale neuronal model. Chaos Solitons Fractals. 2023 Feb; 167:113120.
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Racial/ethnic differences in the relationship between financial worry and white matter hyperintensities in Latinx, Non-Latinx Black, and Non-Latinx White older adults

Published in Neurobiology of Aging, 2023

Socioeconomic status (SES) is associated with white matter hyperintensities (WMHs) and contributes to racial and ethnic health disparities. However, traditional measures of SES may not accurately represent individual financial circumstances among non-Latinx Black and Latinx older adults due to longstanding structural inequities. This study examined associations between multiple SES indicators (education, income, subjective financial worry) and WMHs across non-Latinx Black, Latinx, and non-Latinx White older adults in the Washington Heights-Inwood Columbia Aging Project (N = 662). Latinx participants reported the lowest SES and greatest financial worry, while Black participants evidenced the most WMHs. Greater financial worry was associated with higher WMHs volume above and beyond education and income, which were not associated with WMHs. However, this association was only evident among Latinx older adults. These results provide evidence for the minority poverty hypothesis and highlight the need for systemic socioeconomic interventions to alleviate brain health disparities in older adulthood.

Recommended citation: Morris, EP, Turney, IC, Palms, JD, Zaheed, AB, Sol, K, Amarante, E, Beato, J, Chesebro, AG, Morales, CD, Manly, JJ, Brickman, AM, & Zahodne, LB. Racial/ethnic differences in the relationship between financial worry and white matter hyperintensities in Latinx, Non-Latinx Black, and Non-Latinx White older adults. Neurobiol Aging. 2023 Sep;129:149-156.
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First Aid for the USMLE Step 1 2024

Published in McGraw-Hill, 2024

Recommended citation: Contributing Author. Le, T, Bhushan, V, Qiu, C, Chalise, A, Kaparaliotis, P (eds.). First Aid for the USMLE Step 1 2024. New York: McGraw-Hill. (2024).
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Ketosis regulates K+ ion channels, strengthening brain-wide signaling disrupted by age

Published in Imaging Neuroscience, 2024

Aging is associated with impaired signaling between brain regions when measured using resting-state functional magnetic resonance imaging (fMRI). This age-related destabilization and desynchronization of brain networks reverses itself when the brain switches from metabolizing glucose to ketones. Here, we probe the mechanistic basis for these effects. First, we confirmed their robustness across measurement modalities using two datasets acquired from resting-state EEG (Lifespan: standard diet, 20–80 years, N = 201; Metabolic: individually weight-dosed and calorically-matched glucose and ketone ester challenge, mean = 26.9 +/- 11.2 years, N = 36). Then, using a multiscale conductance-based neural mass model, we identified the unique set of mechanistic parameters consistent with our clinical data. Together, our results implicate potassium (K+) gradient dysregulation as a mechanism for age-related neural desynchronization and its reversal with ketosis, the latter finding of which is consistent with direct measurement of ion channels. As such, the approach facilitates the connection between macroscopic brain activity and cellular-level mechanisms.

Recommended citation: van Nieuwenhuizen, H, Chesebro, AG, Polizu, C, Clarke, K, Strey, HH, Weistuch, C, Mujica-Parodi, LR. Ketosis regulates K+ ion channels, strengthening brain-wide signaling disrupted by age. Imaging Neuroscience. 2024 May; 2:1-14.
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Achieving Occam’s razor: Deep learning for optimal model reduction

Published in PLoS Computational Biology, 2024

All fields of science depend on mathematical models. Occam’s razor refers to the principle that good models should exclude parameters beyond those minimally required to describe the systems they represent. This is because redundancy can lead to incorrect estimates of model parameters from data, and thus inaccurate or ambiguous conclusions. Here, we show how deep learning can be powerfully leveraged to apply Occam’s razor to model parameters. Our method, FixFit, uses a feedforward deep neural network with a bottleneck layer to characterize and predict the behavior of a given model from its input parameters. FixFit has three major benefits. First, it provides a metric to quantify the original model’s degree of complexity. Second, it allows for the unique fitting of data. Third, it provides an unbiased way to discriminate between experimental hypotheses that add value versus those that do not. In three use cases, we demonstrate the broad applicability of this method across scientific domains. To validate the method using a known system, we apply FixFit to recover known composite parameters for the Kepler orbit model and a dynamic model of blood glucose regulation. In the latter, we demonstrate the ability to fit the latent parameters to real data. To illustrate how the method can be applied to less well-established fields, we use it to identify parameters for a multi-scale brain model and reduce the search space for viable candidate mechanisms.

Recommended citation: Antal, BB, Chesebro, AG, Strey, HH, Mujica-Parodi, LR, Weistuch, C. Achieving Occam's Razor: Deep Learning for Optimal Model Reduction. PLoS Comput Biol 20(7): e1012283.
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Role of Metabolism in the Emergence of Neuropsychiatric Disorders

Published in Metabolic Psychiatry. Strüngmann Forum Reports. Springer-Nature, Cham., 2025

Recommended citation: Weistuch, C,* Chesebro, AG,* Antal, B, Mujica-Parodi, LR. 2025. Role of Metabolism in the Emergence of Neuropsychiatric Disorders. In D Öngür & J Ford (Eds.), Metabolic Psychiatry. Strüngmann Forum Reports (J R Lupp, series editor), Springer-Nature, Cham. *equal contributions.
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First Aid for the USMLE Step 1 2025

Published in McGraw-Hill, 2025

Recommended citation: Contributing Author. Le, T, Bhushan, V, Chalise, A, Rivera, CC, Rogner, J (eds.). First Aid for the USMLE Step 1 2025. New York: McGraw-Hill. (2025).
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Brain aging shows nonlinear transitions, suggesting a midlife “critical window” for metabolic intervention

Published in PNAS, 2025

Age-related cognitive decline is associated with metabolic, vascular, and inflammatory changes, making it challenging to distinguish primary causes from secondary (downstream) effects. This study demonstrates that brain aging follows a specific progression, with the first stage occurring in middle age and coinciding with increased insulin resistance. Moreover, we show that brain areas that age fastest are also those most vulnerable to neuronal insulin resistance. Importantly, we find that administering ketones, which can fuel neurons while bypassing insulin resistance, reverses brain aging effects. However, this intervention is only effective when provided early enough for neurons to remain viable. These findings contribute to our understanding of brain aging mechanisms and suggest neurometabolic strategies for targeted early intervention in preventing age-related cognitive decline.

Recommended citation: Antal, BB, van Nieuwenhuizen, H, Chesebro, AG, Jones, DT, Clarke, K, Weistuch, C, Ratai, EM, Dill, KA, Mujica-Parodi, LR. Brain aging shows nonlinear transitions, suggesting midlife “critical window” for metabolic intervention. Proc Natl Acad Sci U S A. 122 (10) e2416433122.
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Challenges and frontiers in computational metabolic psychiatry

Published in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 2025

One of the primary challenges in metabolic psychiatry is that the disrupted brain functions that underlie psychiatric conditions arise from a complex set of downstream and feedback processes that span multiple spatiotemporal scales. Importantly, the same circuit can have multiple points of failure, each of which results in a different type of dysregulation, and thus elicits distinct cascades downstream that produce divergent signs and symptoms. Here, we illustrate this challenge by examining how subtle differences in circuit perturbations can lead to divergent clinical outcomes. We also discuss how computational models can perform the spatially heterogeneous integration and bridge in vitro and in vivo paradigms. By leveraging recent methodological advances and tools, computational models can integrate relevant processes across scales (e.g., tricarboxylic acid cycle, ion channel, neural microassembly, whole-brain macrocircuit) and across physiological systems (e.g., neural, endocrine, immune, vascular), providing a framework that can unite these mechanistic processes in a manner that goes beyond the conceptual and descriptive to the quantitative and generative. These hold the potential to sharpen our intuitions toward circuit-based models for personalized diagnostics and treatment.

Recommended citation: Chesebro, AG, Antal, BB, Weistuch, C, Mujica-Parodi, LR. Challenges and frontiers in computational metabolic psychiatry. Biol Pyschiatry Cogn Neurosci Neuroimaging.  2025 Mar;10(3):258-266.
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Spatially convergent fMRI signatures of diabetes and male sex identify genetic vulnerabilities to accelerated brain aging

Published in Preprint, 2025

Age-related cognitive decline results from complex interactions between neuroendocrine and neurometabolic processes that undergo lifelong degredation, yet the mechanisms underlying these interactions remain poorly understood. This study examined the effects of diabetes and sex on functional brain networks across aging through analysis of two large cohorts (N=1,621 total) using both 3T and 7T functional MRI, complemented by spatial transcriptomic data from over 14,000 genes from six post-mortem brains. Four networks— cingulo-opercular, default mode, salience, and lateral somatomotor—exhibited significant functional decline in both individuals with diabetes and independently in males. Gene expression analysis of vulnerable networks revealed significant overexpression of insulin-dependent glucose transporters, dopaminergic and GABAergic synaptic genes, and VEGFA-VEGFR2 pathway components. These findings suggest functionally-specific circuit vulnerability to metabolic and hormonal dysregulation, potentially offering targets for early intervention before irreversible neurodegeneration occurs.

Recommended citation: Chesebro, AG,* Rohm, LR,* Antal, BB, Weistuch, C, Jones, DT, Strey, HH, Ratai, EM, Mujica-Parodi, LR. Spatially convergent fMRI signatures of diabetes and male sex highlight genetic vulnerabilities to accelerated brain aging. (Submitted May 2025). Preprint.
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Increasing spectral DCM flexibility and speed by leveraging Julia’s ModelingToolkit and automated differentiation

Published in Imaging Neuroscience, 2025

Using neuroimaging and electrophysiological data to infer neural parameter estimations from theoretical circuits requires solving the inverse problem. Here, we provide a new Julia language package designed to i) compose complex dynamical models in a simple and modular way with ModelingToolkit.jl, ii) implement parameter fitting based on spectral dynamic causal modeling (sDCM) using the Laplace approximation, analogous to MATLAB implementation in SPM, and iii) leverage Julia’s unique strengths to increase accuracy and speed by employing Automatic Differentiation during the fitting procedure. To illustrate the utility of our flexible modular approach, we provide a method to improve correction for fMRI scanner field strengths (1.5T, 3T, 7T) when fitting models to real data.

Recommended citation: Hofmann, D, Chesebro, AG, Rackauckas, C, Mujica-Parodi, LR, Friston, KJ, Edelman, A, Strey, HH. Increasing spectral DCM flexibility and speed by leveraging Julia’s ModelingToolkit and automated differentiation.Imaging Neuroscience. 2025; 3 IMAG.a.88.
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Methods for Machine Learning in Chaotic Systems

Published in US Provisional Patent, 2025

Recommended citation: Chesebro, AG, Hofmann, D, Miller, EK, Granger, RH, Edelman, A, Rackauckas, CV, Mujica-Parodi, LR, Strey, HH. "Methods for Machine Learning in Chaotic Systems." US Provisional Patent. Filed June 2025.
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Scientific machine learning of chaotic systems discovers governing equations for neural populations

Published in Preprint, 2025

Discovering governing equations that describe complex chaotic systems remains a fundamental challenge in physics and neuroscience. Here, we introduce the PEM-UDE method, which combines the prediction-error method with universal differential equations to extract interpretable mathematical expressions from chaotic dynamical systems, even with limited or noisy observations. This approach succeeds where traditional techniques fail by smoothing optimization landscapes and removing the chaotic properties during the fitting process without distorting optimal parameters. We demonstrate its efficacy by recovering hidden states in the Rossler system and reconstructing dynamics from noise-corrupted electrical circuit data, where the correct functional form of the dynamics is recovered even when one of the observed time series is corrupted by noise 5x the magnitude of the true signal. We demonstrate that this method is capable of recovering the correct dynamics, whereas direct symbolic regression methods, such as SINDy, fail to do so with the given amount of data and noise. Importantly, when applied to neural populations, our method derives novel governing equations that respect biological constraints such as network sparsity - a constraint necessary for cortical information processing yet not captured in next-generation neural mass models - while preserving microscale neuronal parameters. These equations predict an emergent relationship between connection density and both oscillation frequency and synchrony in neural circuits. We validate these predictions using three intracranial electrode recording datasets from the medial entorhinal cortex, prefrontal cortex, and orbitofrontal cortex. Our work provides a pathway to develop mechanistic, multi-scale brain models that generalize across diverse neural architectures, bridging the gap between single-neuron dynamics and macroscale brain activity.

Recommended citation: Chesebro, AG, Hofmann, D, Dixit, V, Miller EK, Granger RH, Edelman, A, Rackauckas CV, Mujica-Parodi, LR, Strey, HH. Scientific machine learning for chaotic systems discovers governing equations in neural populations. (Submitted July 2025). Preprint.
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Mechanistic signatures of comorbid PTSD with cognitive impairment implicate cortisol-induced neural toxicity

Published in Neuropsychopharmacology, 2026

The men and women who worked in rescue and recovery operations at the 9/11 World Trade Center site are developing cognitive impairment (CI) at mid-life, decades before CI is usually detected. To date, one of the most consistent risk factors for CI in this population is symptoms of post-traumatic stress disorder (PTSD). However, little is known about the mechanistic cascade that drives stress-related neurological changes to accelerate cognitive decline in the human brain. We used machine learning to identify distinct brain signatures from functional magnetic resonance imaging between trauma-exposed healthy controls (TEHC; N = 30; 21 men), PTSD without CI (PTSD-CI; N = 19; 16 men), and PTSD with CI (PTSD + CI; N = 22; 18 men). We compared the spatial gradient of each functional signature to the distribution of mRNA expression in the brain. We applied structural equation modeling (SEM) to infer mechanistic cascades specific to each group. While modest accuracy was achieved for the PTSD-CI versus TEHC signature (0.67), clear differentiation was observed for PTSD + CI versus TEHC (0.73) and PTSD + CI versus PTSD-CI (0.85). Consistent significant correlations were found between PTSD + CI signatures and ZNF48, TOMM40, and GRIN1 expression distributions. The cortisol-induced neurotoxicity pathway was consistently found with the PTSD + CI signature, while the p53 signaling pathway was observed across all PTSD signatures. Our results reinforce peripheral biomarkers from a previous transcriptomic study and suggest functional biomarkers in PTSD and PTSD-related CI. Furthermore, our SEM results suggest that PTSD and PTSD-related CI may diverge at the mechanistic level, with neurotoxicity being specific to CI.

Recommended citation: Kuang, Z, Chesebro, AG, Strey, SG, Clouston, SAP, Luft, BJ, Mujica-Parodi, LR. Mechanistic signatures of comorbid PTSD with cognitive impairment implicate cortisol-induced neural toxicity. Neuropsychopharmacology. 2026 Feb 12.
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PEM-UDE for neural mass models

Published:

Chesebro, AG, Strey, HH. (2025, July). Oral presentation at JuliaCon (Annual Conference for Julia Programming Language) 2025.

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