Title: Cognitive Impairment in Long Covid: PhEnotyping and RehabilitatiOn (CICERO)
Funder: Department of Health and Social Care

Abstract: Cognitive impairment is present in 25-75% of people with long Covid, but little is known about its nature, or treatment options. The loss of functional ability has major consequences for affected people, families and the wider economy and the huge number of people with long Covid makes this a top priority issue for health services worldwide. This study aims to phenotype &ldquo;cognitive Covid&rdquo; and deliver cognitive rehabilitation to help recovery. In Workstream 1 we will establish the phenotype of cognitive Covid. First, we will identify aspects of cognitive function that are most affected. The test battery will include traditional tests, encompassing all principal cognitive domains including memory, attention and executive function. Given that the medial temporal lobe (MTL) is vulnerable to direct infiltration by SARS-CoV-2, we will additionally use the Neotiv app-based tests to probe memory processes subserved by the MTL that are not examined with traditional tests. Second, we will determine how the cognitive impairment is modulated by other aspects of long Covid, namely fatigue, anxiety/depression and sleep disturbance. Third, we will identify the imaging correlates of cognitive Covid, using MRI to measure whole brain and MTL volume, functional and structural connectivity. Workstream 2 will use cognitive rehabilitation to help recovery from cognitive Covid. The rehabilitation programme will focus on those cognitive domains found in Workstream 1 to be most affected, including remediation, compensatory and adaptive strategies and co-produced with PPI input. We will deliver a &ldquo;Covid-19 Cognitive Recovery Guide&rdquo; for patients and clinicians. An RCT (n=118) will compare the intervention (rehabilitation) against standard of care, with the primary outcome being participant-set goals. Secondary outcomes will be measures of cognition, quality of life, MRI structure and connectivity. Health economic benefits of treatment will be assessed in terms of health resource utilisation, primary (cost per QALY) and secondary cost-effectiveness analyses.

Lay abstract: Cognitive impairment is increasingly recognised as a major component of long Covid, estimated to be present in 25-75% of affected individuals. This impairment impacts quality of life and the loss of functional ability has major consequences for affected people, their families and the wider economy given people s difficulty in returning to work. We propose a two-stage study for investigation and treatment of &ldquo;cognitive Covid&rdquo;. Stage 1 will determine those aspects of cognitive function that are particularly affected in cognitive Covid and the severity of the impairment. We will also explore the relationship between cognitive impairment and other aspects of long Covid, namely fatigue, anxiety, depression and sleep disturbance. MRI scanning will be used to measure brain structure and connectivity, to identify the brain networks affected in cognitive Covid that may underpin the cognitive dysfunction. Stage 2 will focus on helping people recover from cognitive Covid. This will involve use of rehabilitation strategies aimed at improving function in those cognitive functions identified in Stage 1 as being most affected, and assessing the benefit of rehabilitation on quality of life and people s ability to return to everyday function. These strategies will be co-produced in collaboration with a group of people living with cognitive Covid. At the end of Stage 2 we will produce a freely available &ldquo;Covid- 19 Cognitive Recovery Guide&rdquo; for affected people, their close contacts and clinicians. In conclusion, cognitive impairment is frequently observed in long Covid but at present little is understood about its nature, or how it can be treated. The sheer scale of the CV19 pandemic makes this a top priority unmet need for healthcare worldwide. The aim of this study is to meet this need and to deliver a treatment plan for affected people which will help them return to normal life and working ability.

Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: INFECTION;NEUROLOGICAL