Browsing by Author "Hughes, Timothy M."

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    Associations among plasma, MRI, and amyloid PET biomarkers of Alzheimer's disease and related dementias and the impact of health‐related comorbidities in a community‐dwelling cohort
    (Wiley, 2024) Rudolph, Marc D.; Sutphen, Courtney L.; Register, Thomas C.; Whitlow, Christopher T.; Solingapuram Sai, Kiran K.; Hughes, Timothy M.; Bateman, James R.; Dage, Jeffrey L.; Russ, Kristen A.; Mielke, Michelle M.; Craft, Suzanne; Lockhart, Samuel N.; Neurology, School of Medicine
    Introduction: We evaluated associations between plasma and neuroimaging-derived biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities. Methods: We examined plasma biomarkers (neurofilament light chain, glial fibrillary acidic protein, amyloid beta [Aβ] 42/40, phosphorylated tau 181) and neuroimaging measures of amyloid deposition (Aβ-positron emission tomography [PET]), total brain volume, white matter hyperintensity volume, diffusion-weighted fractional anisotropy, and neurite orientation dispersion and density imaging free water. Participants were adjudicated as cognitively unimpaired (CU; N = 299), mild cognitive impairment (MCI; N = 192), or dementia (DEM; N = 65). Biomarkers were compared across groups stratified by diagnosis, sex, race, and APOE ε4 carrier status. General linear models examined plasma-imaging associations before and after adjusting for demographics (age, sex, race, education), APOE ε4 status, medications, diagnosis, and other factors (estimated glomerular filtration rate [eGFR], body mass index [BMI]). Results: Plasma biomarkers differed across diagnostic groups (DEM > MCI > CU), were altered in Aβ-PET-positive individuals, and were associated with poorer brain health and kidney function. Discussion: eGFR and BMI did not substantially impact associations between plasma and neuroimaging biomarkers. Highlights: Plasma biomarkers differ across diagnostic groups (DEM > MCI > CU) and are altered in Aβ-PET-positive individuals. Altered plasma biomarker levels are associated with poorer brain health and kidney function. Plasma and neuroimaging biomarker associations are largely independent of comorbidities.
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    Chronic neuropsychiatric sequelae of SARS-CoV-2: Protocol and methods from the Alzheimer's Association Global Consortium
    (Alzheimer’s Association, 2022-09-22) de Erausquin, Gabriel A.; Snyder, Heather; Brugha, Traolach S.; Seshadri, Sudha; Carrillo, Maria; Sagar, Rajesh; Huang, Yueqin; Newton, Charles; Tartaglia, Carmela; Teunissen, Charlotte; Håkanson, Krister; Akinyemi, Rufus; Prasad, Kameshwar; D'Avossa, Giovanni; Gonzalez-Aleman, Gabriela; Hosseini, Akram; Vavougios, George D.; Sachdev, Perminder; Bankart, John; Ole Mors, Niels Peter; Lipton, Richard; Katz, Mindy; Fox, Peter T.; Katshu, Mohammad Zia; Iyengar, M. Sriram; Weinstein, Galit; Sohrabi, Hamid R.; Jenkins, Rachel; Stein, Dan J.; Hugon, Jacques; Mavreas, Venetsanos; Blangero, John; Cruchaga, Carlos; Krishna, Murali; Wadoo, Ovais; Becerra, Rodrigo; Zwir, Igor; Longstreth, William T.; Kroenenberg, Golo; Edison, Paul; Mukaetova-Ladinska, Elizabeta; Staufenberg, Ekkehart; Figueredo-Aguiar, Mariana; Yécora, Agustín; Vaca, Fabiana; Zamponi, Hernan P.; Lo Re, Vincenzina; Majid, Abdul; Sundarakumar, Jonas; Gonzalez, Hector M.; Geerlings, Mirjam I.; Skoog, Ingmar; Salmoiraghi, Alberto; Boneschi, Filippo Martinelli; Patel, Vibuthi N.; Santos, Juan M.; Arroyo, Guillermo Rivera; Moreno, Antonio Caballero; Felix, Pascal; Gallo, Carla; Arai, Hidenori; Yamada, Masahito; Iwatsubo, Takeshi; Sharma, Malveeka; Chakraborty, Nandini; Ferreccio, Catterina; Akena, Dickens; Brayne, Carol; Maestre, Gladys; Williams Blangero, Sarah; Brusco, Luis I.; Siddarth, Prabha; Hughes, Timothy M.; Ramírez Zuñiga, Alfredo; Kambeitz, Joseph; Laza, Agustin Ruiz; Allen, Norrina; Panos, Stella; Merrill, David; Ibáñez, Agustín; Tsuang, Debby; Valishvili, Nino; Shrestha, Srishti; Wang, Sophia; Padma, Vasantha; Anstey, Kaarin J.; Ravindrdanath, Vijayalakshmi; Blennow, Kaj; Mullins, Paul; Łojek, Emilia; Pria, Anand; Mosley, Thomas H.; Gowland, Penny; Girard, Timothy D.; Bowtell, Richard; Vahidy, Farhaan S.; Psychiatry, School of Medicine
    Introduction: Coronavirus disease 2019 (COVID-19) has caused >3.5 million deaths worldwide and affected >160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID-19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID-19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID-19 to neurologic illness, both short and long term. Methods: This article describes what is known so far in terms of links among COVID-19, the brain, neurological symptoms, and Alzheimer's disease (AD) and related dementias. We focus on risk factors and possible molecular, inflammatory, and viral mechanisms underlying neurological injury. We also provide a comprehensive description of the Alzheimer's Association Consortium on Chronic Neuropsychiatric Sequelae of SARS-CoV-2 infection (CNS SC2) harmonized methodology to address these questions using a worldwide network of researchers and institutions. Results: Successful harmonization of designs and methods was achieved through a consensus process initially fragmented by specific interest groups (epidemiology, clinical assessments, cognitive evaluation, biomarkers, and neuroimaging). Conclusions from subcommittees were presented to the whole group and discussed extensively. Presently data collection is ongoing at 19 sites in 12 countries representing Asia, Africa, the Americas, and Europe. Discussion: The Alzheimer's Association Global Consortium harmonized methodology is proposed as a model to study long-term neurocognitive sequelae of SARS-CoV-2 infection. Key points: The following review describes what is known so far in terms of molecular and epidemiological links among COVID-19, the brain, neurological symptoms, and AD and related dementias (ADRD)The primary objective of this large-scale collaboration is to clarify the pathogenesis of ADRD and to advance our understanding of the impact of a neurotropic virus on the long-term risk of cognitive decline and other CNS sequelae. No available evidence supports the notion that cognitive impairment after SARS-CoV-2 infection is a form of dementia (ADRD or otherwise). The longitudinal methodologies espoused by the consortium are intended to provide data to answer this question as clearly as possible controlling for possible confounders. Our specific hypothesis is that SARS-CoV-2 triggers ADRD-like pathology following the extended olfactory cortical network (EOCN) in older individuals with specific genetic susceptibility. The proposed harmonization strategies and flexible study designs offer the possibility to include large samples of under-represented racial and ethnic groups, creating a rich set of harmonized cohorts for future studies of the pathophysiology, determinants, long-term consequences, and trends in cognitive aging, ADRD, and vascular disease. We provide a framework for current and future studies to be carried out within the Consortium. and offers a "green paper" to the research community with a very broad, global base of support, on tools suitable for low- and middle-income countries aimed to compare and combine future longitudinal data on the topic. The Consortium proposes a combination of design and statistical methods as a means of approaching causal inference of the COVID-19 neuropsychiatric sequelae. We expect that deep phenotyping of neuropsychiatric sequelae may provide a series of candidate syndromes with phenomenological and biological characterization that can be further explored. By generating high-quality harmonized data across sites we aim to capture both descriptive and, where possible, causal associations.
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    Relation of Atrial Fibrillation to Cognitive Decline (from the REasons for Geographic and Racial Differences in Stroke [REGARDS] Study)
    (Elsevier, 2021) Bailey, Margie J.; Soliman, Elsayed Z.; McClure, Leslie A.; Howard, George; Howard, Virginia J.; Judd, Suzanne E.; Unverzagt, Fred; Wadley, Virginia; Sachs, Bonnie C.; Hughes, Timothy M.; Psychiatry, School of Medicine
    The association of atrial fibrillation (AF) with cognitive function remains unclear, especially among racially/geographically diverse populations. This analysis included 25,980 black and white adults, aged 48+, from the national REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, free from cognitive impairment and stroke at baseline. Baseline AF was identified by self-reported medical history or electrocardiogram (ECG). Cognitive testing was conducted yearly with the Six Item Screener (SIS) to define impairment and at 2-year intervals to assess decline on: animal naming and letter fluency, Montreal Cognitive Assessment (MoCA), Word List Learning (WLL) and Delayed Recall tasks (WLD). Multivariable regression models estimated the relationships between AF and baseline impairment and time to cognitive impairment. Models were adjusted sequentially for age, sex, race, geographic region, and education, then cardiovascular risk factors and finally incident stroke. AF was present in 2,168 (8.3%) participants at baseline. AF was associated with poorer baseline performance on measures of: semantic fluency (p<0.01); global cognitive performance (MoCA, p<0.01); and WLD (p<0.01). During a mean follow-up of 8.06 years, steeper declines in list learning were observed among participants with AF (p<0.03) which remained significant after adjusting for cardiovascular risk factors (p<0.04) and incident stroke (p<0.03). Effect modification by race, sex and incident stroke on AF and cognitive decline were also detected. In conclusion, AF was associated with poorer baseline cognitive performance across multiple domains and incident cognitive impairment in this bi-racial cohort. Additional adjustment for cardiovascular risk factors attenuated these relations with the exception of learning.