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Chronic neuropsychiatric sequelae of SARS-CoV-2: Protocol and methods from the Alzheimer's Association Global Consortium

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; Mors, Niels Peter Ole; 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.; Re, Vincenzina Lo; Majid, Abdul; Sundarakumar, Jonas; Gonzalez, Hector M.; Geerlings, Mirjam I.; Skoog, Ingmar; Salmoiraghi, Alberto; Bo...


Gabriel A. de Erausquin

Heather Snyder

Traolach S. Brugha

Sudha Seshadri

Maria Carrillo

Rajesh Sagar

Yueqin Huang

Charles Newton

Carmela Tartaglia

Charlotte Teunissen

Krister Håkanson

Rufus Akinyemi

Kameshwar Prasad

Giovanni D'Avossa

Gabriela Gonzalez‐Aleman

Akram Hosseini

George D. Vavougios

Perminder Sachdev

John Bankart

Niels Peter Ole Mors

Richard Lipton

Mindy Katz

Peter T. Fox

Mohammad Zia Katshu

M. Sriram Iyengar

Galit Weinstein

Hamid R. Sohrabi

Rachel Jenkins

Dan J. Stein

Jacques Hugon

Venetsanos Mavreas

John Blangero

Carlos Cruchaga

Murali Krishna

Ovais Wadoo

Rodrigo Becerra

Igor Zwir

William T. Longstreth

Golo Kroenenberg

Paul Edison

Elizabeta Mukaetova‐Ladinska

Ekkehart Staufenberg

Mariana Figueredo‐Aguiar

Agustín Yécora

Fabiana Vaca

Hernan P. Zamponi

Vincenzina Lo Re

Abdul Majid

Jonas Sundarakumar

Hector M. Gonzalez

Mirjam I. Geerlings

Ingmar Skoog

Alberto Salmoiraghi

Filippo Martinelli Boneschi

Vibuthi N. Patel

Juan M. Santos

Guillermo Rivera Arroyo

Antonio Caballero Moreno

Pascal Felix

Carla Gallo

Hidenori Arai

Masahito Yamada

Takeshi Iwatsubo

Malveeka Sharma

Nandini Chakraborty

Catterina Ferreccio

Dickens Akena

Carol Brayne

Gladys Maestre

Sarah Williams Blangero

Luis I. Brusco

Prabha Siddarth

Timothy M. Hughes

Alfredo Ramírez Zuñiga

Joseph Kambeitz

Agustin Ruiz Laza

Norrina Allen

Stella Panos

David Merrill

Agustín Ibáñez

Debby Tsuang

Nino Valishvili

Srishti Shrestha

Sophia Wang

Vasantha Padma

Kaarin J. Anstey

Vijayalakshmi Ravindrdanath

Kaj Blennow

Paul Mullins

Emilia Łojek

Anand Pria

Thomas H. Mosley

Timothy D. Girard

Farhaan S. Vahidy


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.

Journal Article Type Article
Acceptance Date Jun 14, 2022
Online Publication Date Sep 22, 2022
Publication Date Sep 22, 2022
Deposit Date Feb 4, 2023
Publicly Available Date Feb 8, 2023
Journal Alzheimer's and Dementia: Translational Research and Clinical Interventions
Print ISSN 2352-8737
Electronic ISSN 2352-8737
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 8
Issue 1
Article Number e12348
Keywords Cognitive impairment, dementia, neuropsychiatric sequelae, predictors, SARS‐CoV‐2
Public URL
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Chronic neuropsychiatric sequelae of SARS‐CoV‐2: Protocol and methods from the Alzheimer's Association Global Consortium (2.5 Mb)

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This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

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