BACKGROUND OF PROPOSED INVESTIGATION

Overview

A heterogenous cohort of patients, who have been variably denoted as suffering from "Long
COVID" or the Post COVID-19 Syndrome, will have persistent cognitive and affective
symptoms. A recent large systematic review found that fatigue and objective cognitive
impairment were common and persistent after COVID-19 disease with a prevalence of 24.4%
and 20.2% respectively (Badenoch et al., 2022). The severity of physical illness
associated with SARS-CoV2 infection does not correlate with the likelihood of these
symptoms developing or persisting, raising the questions as to the nature of the
processes driving post COVID-19 cognitive symptoms.

The effects of COVID-19 disease on the brain and the link to cognitive impairment has
been emphasised as an area of priority research (Samkaria and Mandal, 2021). There have
been proposed mechanistic explanations from case studies (Yesilkaya et al., 2021) as well
as more general commentaries on the neuroimmune correlates of COVID-19 disease,
(Yesilkaya and Balcioglu, 2020) but as yet no high-quality evidence exists.

It is suggested that COVID-19 disease may lead to pathologically identifiable brain
changes. A large study evaluating structural brain imaging of patients before and after
SARS-CoV2 infection using United Kingdom (UK) Biobank data found evidence of grey matter
volume reduction compared with controls (Douaud et al., 2022). This mainly involved
olfactory areas but wider limbic involvement was discussed in the context of memory
impairment and reported cognitive change. A much smaller study (Hosp et al., 2021)
correlated functional imaging changes, Fluoro-Deoxy-Glucose Positron Emission Tomography
(FDG-PET), with cognitive impairment in patients hospitalised with COVID-19 disease.

Magnetic Resonance Spectroscopy (MRS) is an imaging technology that represents a
non-invasive diagnostic tool for evaluating white matter injury in the brain and can
provide valuable information regarding underlying pathogenesis. Most importantly, MRS can
identify neurochemical abnormalities even in the absence of corresponding findings on
structural MR brain imaging. This is important, in that many patients with persistent
cognitive symptoms have normal conventional imaging (Hellgren et al., 2021).

MRS has been used in a small preliminary study to outline brain inflammation and damage
linked to COVID-19 disease (Rapalino et al., 2021). This work pointed to characteristic
white matter inflammatory MRS findings in patients with severe and acute COVID-19
disease. White matter changes have also been described using conventional MR imaging in
patients presenting with cognitive impairment in association with COVID-19 disease
(Hellgren et al., 2021) but such results were not replicated in patients describing
"brain fog" symptoms after hospitalisation for COVID-19 disease (Sklinda et al., 2021).

Reviewing the nascent investigation already undertaken, there is a possibility that
inflammation and other neural correlates play a role in persistent cognitive symptoms in
those who have been infected with SARS-CoV2. This pilot study aims to investigate these
links as a necessary and urgent first step in trying to understand how and why a
significant number of patients are affected in this way.

Local relevance

NHS Grampian, along with the other health boards in Scotland, has received funding from
the Scottish Government to identify and provide intervention for the mental health needs
of patients hospitalised with COVID-19 disease. This follows on from Coronavirus
(Covid-19): Mental health needs of hospitalised patients - report
(https://www.gov.scot/publications/mental-health-needs-patients-hospital…
/).

This has been identified as an unmet need and a clinical priority. The response has seen
the creation of the Mental Health After Covid-19 Hospitalisation Team (MACH). NHS
Grampian is amongst a small leading group of other boards in rolling out this service and
clinicians are currently contacting eligible patients to offer screening appointments as
well as developing mental health interventions.

NHS Grampian is also moving forward with resources to help staff affected by COVID-19
disease. NHS Grampian's "We Care" programme is expanding to address the identified needs
of staff affected by the pandemic, which will include the better identification,
understanding and management of 'Long COVID'. There is therefore a significant overlap in
the NHS Grampian corporate response for staff and the wider clinical strategy. This
underlines the importance and centrality of addressing the longer-term effects of
COVID-19 disease for both staff and patients alike.

Embedding research within the scope of the work of the MACH team is very important. There
is a lot that remains unknown about the COVID-19 disease and meaningful inquiry about
associated long term effects is an important and pressing issue.

Patients suffering with the long-term sequelae of COVID-19 disease will have a range of
needs. In particular, a pressing concern for them is cognitive change. Within NHS
Grampian there have been reports anecdotally from significant numbers of patients who
have been seen in the MACH clinics so far. The prevalence of cognitive change,
specifically impaired recall, has been estimated at 25% of patients from 12 to 18 months
after SARS-CoV2 infection (Becker et al., 2021). In a recent large meta-analysis it was
found that 32% of patients reported fatigue and 22% had evidence of cognitive impairment
12 weeks or more after SARS-CoV2 infection (Ceban et al., 2022).

Investigators plan to offer neuropsychometric testing to all patients who report
persistent cognitive symptoms in order to better understand the particular pattern, or
phenotype, encountered by patients. It will be important to consider why it is that some
patients report prolonged symptoms in general and prolonged cognitive symptoms
specifically. Neuroimaging, and spectroscopy specifically, could start to provide answers
to these questions.

The proposed project will enable research into a common adverse outcome of COVID-19
disease, which has both national recognition and significant morbidity (Ceban et al.,
2022).