Chronic neuropsychiatric sequelae of SARS‐CoV‐2: Protocol and methods from the Alzheimer's Association Global Consortium
Authors: 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 , 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 , Blangero Sarah Williams , Brusco Luis I. , Siddarth Prabha , Hughes Timothy M. , Zuñiga Alfredo Ramírez , 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. 
Published: September 2022

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.