Assessing Cognitive Deterioration in COVID-19 (ACDC) Cognitive Impairment After COVID-19 - Inflammatory and Neural Correlates: A Pilot Study
Conditions: SARS-CoV-2 Infection, Cognitive Change, Cognitive Dysfunction
Sponsor: NHS Grampian

 
 
 
 
The ACDC study: 
Assessing Cognitive Deterioration in COVID-19 
Protocol V1  18th August 2022 
IRAS PROJECT ID: 314094 
 
 
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Centre: Aberdeen 
 
 
 
IRAS Project ID: 314094 
 
 
 
Cognitive Impairment after COVID-19 - Inflammatory 
and Neural Correlates: A pilot study 
The ACDC study: 
Assessing Cognitive Deterioration in COVID-19 
 
 
 
Sponsor 
NHS Grampian  
Funder 
NHS Grampian Endowments 
Chief Investigator 
Dr Jonathan McLaughlin 
Sponsor number 
1-050-22 
Version Number and Date 
Version 1 18/8/2022 
 
 
 
 
 
 
 
 

 
 
The ACDC study: 
Assessing Cognitive Deterioration in COVID-19 
Protocol V1  18th August 2022 
IRAS PROJECT ID: 314094 
 
 
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List of Abbreviations 
 
AMARES 
Advanced Method for Accurate, Robust and Efficient Spectral fitting of MRS 
data with use of prior knowledge 
CI 
Chief Investigator 
CNORIS 
Clinical Negligence and Other Risks Scheme 
COVID-19  
Coronavirus Disease 2019 
CRF 
Case Report Form 
DMC 
Data Monitoring Committee 
DTI 
Diffusion Tensor Imaging 
DWI 
Diffusion Weighted Imaging  
FDG-PET 
Fluoro-Deoxy-Glucose Positron Emission Tomography 
FLAIR 
Fluid Attenuated Inversion Recovery  
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulations  
GP  
General Practitioner 
HRA 
Health Research Authority 
ISF 
Investigator Site File 
MACH 
Mental Health After COVID-19 Hospitalisation 
MRI 
Magnetic Resonance Imaging 
MRS 
Magnetic Resonance Spectroscopy 
mTBI 
Mild Traumatic Brain Injury 
NHS  
National Health Service 
PCR 
Polymerase Chain Reaction 
PI 
Principal Investigator 
PMG 
Project Management Group 
PRESS 
Point RESolved Spectroscopy  
QSM 
Quantitative Susceptibility Mapping 
R&D 
Research and Development 
REC 
Research Ethics Committee 
SARS-CoV2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SOP 
Standard Operating Procedure 
SWI 
Susceptibility Weighted Imaging  
TBSS 
Tract Based Spatial Statistics  
TMF/SMF 
Trial/Study Master File 
TSC 
Trial/Study Steering Committee 
 

 
 
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PROTOCOL SUMMARY 
 
 
CONSIDERED 
FOR ENTRY 
Patients Hospitalised for COVID-19 (with a positive PCR for 
COVID-19) in NHS Grampian who subjectively report, and are 
found to have evidence of, cognitive impairment on 
Neuropsychological assessment.  
TRIAL ENTRY 
Patients will be screened for eligibility.  Written consent will be 
sought prior to the study. 
OUTCOME 
ASSESSMENT 
MR imaging and spectroscopy to outline possible inflammation 
and neural correlates of cognitive impairment post COVID-19 
hospitalisation. 
CO-ORDINATION 
Day to Day:  by the Research Nurse 
Overall:  Chief Investigator 
FUNDER 
NHS Grampian Endowment Fund; Florence Cumming 
Bequest  
TIME TABLE 
Start date: 
Planned finish date: 
Planned start of recruitment: 
Planned end of recruitment: 
September 2022 
September 2024 
September 2022 
September2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BACKGROUND OF PROPOSED INVESTIGATION 
 

 
 
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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.  
 

 
 
The ACDC study: 
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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-hospitalised-due-
covid-19/).  
 
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 we 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 we have heard this reported anecdotally by 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).  
 
We 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).  
 

 
 
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STUDY AIMS AND OBJECTIVES 
 
AIMS 
 

 
 
The ACDC study: 
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IRAS PROJECT ID: 314094 
 
 
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• 
To document brain structure and metabolism via spectroscopy in patients who 
have been hospitalised with COVID-19 disease and who subjectively and 
objectively evidence cognitive impairment 
• 
To assess cognitive performance in patients reporting cognitive deterioration 
following hospitalisation for COVID-19 disease 
• 
To outline associations between MR Imaging and spectroscopy data and 
cognitive test performance  
 
Primary Objective 
To report the association (present or not) between MR imaging and spectroscopy 
measures and cognitive performance following hospitalisation for COVID-19 disease. 
 
Secondary Objectives 
To report the level of cognitive performance as measured by formal neuropsychometric 
assessment. 
 
 
 
ENDPOINTS 
 
Primary Endpoint 
 
The primary endpoint is MR imaging and spectroscopy associations with measured 
cognitive performance. 
 
Secondary Endpoint 
 
• 
Metabolic profile of selected brain regions via MRS 
• 
White matter assessment via Tract Based Spatial Statistics (TBSS) 
• 
Brain iron levels (proxy for inflammation) in regions reported to be related to 
memory performance  
 
 
 
 
STUDY DESIGN 
 
The project will be a pilot study. The study is cross-sectional in design. 
 
The study design and outcomes measures are illustrated in Figure 1.  
 
 
 
 
 
 
Figure 1 
 
 
 
Patients hospitalised for COVID-19 disease in NHS Grampian  

 
 
The ACDC study: 
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Protocol V1  18th August 2022 
IRAS PROJECT ID: 314094 
 
 
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IDENTIFYING PARTICIPANTS 
 
Potential participants will be identified by the Mental Health After COVID-19 
Hospitalisation Team (MACH) who will discuss the research with the patient. This will 
be done at an in-person or remote mental health screening appointment for patients 
who have opted in and have returned mental health and cognitive change screening 
measures. This represents standard care and is not study specific screening. 
Similarly, all patients who report cognitive change are being offered 
neuropsychometric testing as part of standard care. The screening measures used 
are as follows: 
Identified patients as above asked to opt-in to Screening appointment by Mental 
Health After COVID-19 Hospitalisation Team (MACH). Screening measures 
undertaken ahead of appointment. Patients reporting cognitive change offered 
formal neuropsychometric assessment as part of service. 
Assessed for eligibility and invited to participate in ACDC study - written 
informed consent obtained. 
Consent 
(n=30) 
 
Brain MR imaging and spectroscopy   
 
MR imaging protocol undertaken 
  

 
 
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EQ-5D-5L Health Questionnaire 
FACIT Fatigue Scale (version 4)  
Psychological and Cognitive Changes since having COVID-19 
Cognitive Change Index (CCI-20-S) 
GAD-7 Anxiety 
PHQ-9 Depression 
Core-10 questionnaire 
Trauma screening questionnaire (TSQ) 
 
On attending their standard of care screening appointment any patient who meets 
the eligibility criteria for the study will be provided with a Participant Information 
Leaflet outlining the purpose of the research along with an Invitation Letter and 
several ways of contacting the research team: a pre-paid reply envelope, an email 
address (gram.mach@nhs.scot) and the telephone number of the MACH team 
(01224 551998). All patients who report cognitive change will be offered 
neuropsychometric testing as part of standard care. This will be organised after the 
initial screening appointment for eligible patients. This neuropsychometric testing will 
be undertaken at a further standard of care appointment and it will be face to face. 
The following neuropsychological tests are to be undertaken:  
 
• 
Wechsler Test of Adult Reading (WTAR) 
• 
California Verbal Learning Test, Third Edition. (CVLT-3) 
• 
The Logical Memory subtest of the Wechsler Memory Scale, 4th Edition 
(WMS-I) 
• 
Rey-Osterrieth Complex Figure Test (ROCFT) 
• 
Digits Backwards & Forwards Span from the Wechsler Memory Scale, 4th 
Edition (WMS-IV) 
• 
Elevator Counting & Elevator Counting with Distraction subtests of the Test of 
Everyday Attention (TEA) 
• 
Verbal Fluency Subtest of the Delis-Kaplan Executive Functioning System (D-
KEFS) 
• 
Hayling & Brixton Tests 
• 
Zoo Map Subtest of the Behavioural Assessment of Dysexecutive Syndrome 
(BADS 
• 
Colour Trails Test 
 
Premorbid Functioning  
Wechsler Test of Adult Reading (WTAR) 
This is a measure of pre-morbid functioning as vocabulary strongly correlates with 
overall ability level and is relatively unaffected by most non-aphasic brain disorders. 
50 irregular words are presented and individuals’ ability to correctly pronounce them 
suggests prior knowledge of them. The WTAR was co-normed among a US and UK 
sample for ages 16-89 years.  
 
 
Memory 
California Verbal Learning Test, Third Edition. (CVLT-3) 
This measures both immediate and delayed memory abilities. The examiner reads 
List A words 5 times, followed by an interference List B. Participants engage in ‘free’ 

 
 
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Protocol V1  18th August 2022 
IRAS PROJECT ID: 314094 
 
 
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and ‘cued’ recall of List A items. Thereafter, there is a 20 minute ‘long delay’ which 
measures recall of List A under the same two conditions of ‘free’ and ‘cued’. The 
measure was created to assess the use of semantic associations when learning 
words and as a screen for memory impairments. The 3rd edition was standardised 
on a large sample of adults (ages 16-90) based on the 2015 US Census data.  
 
The Logical Memory subtest of the Wechsler Memory Scale, 4th Edition (WMS-I).  
This test measures verbal memory and learning. Individuals are told a story and they 
are required to recall as much as possible immediately and after a 20–30-minute 
delay. The test is sensitive to detect subtle memory changes among individuals with 
mild cognitive impairment. 
 
Rey-Osterrieth Complex Figure Test (ROCFT)  
This primarily measures visual memory and visual-spatial constructional ability. 
Participants are shown a complex figure and asked to copy it, then the original image 
is removed. Participants complete an immediate recall followed by a delayed recall of 
20-30 minutes. Internal reliability coefficients [Cronbach alpha (α)] for copy condition 
is greater than α =0.60, and greater than α =0.80 for both immediate and delayed 
recall conditions. 
 
Digits Backwards & Forwards Span from the Wechsler Memory Scale, 4th Edition 
(WMS-IV) 
This will measure working memory.  
 
Attention 
Elevator Counting & Elevator Counting with Distraction subtests of the Test of 
Everyday Attention (TEA) 
These two subtests are widely used clinically and are ecologically valid measures of 
sustained and selective attention. During elevator counting, individuals establish 
which imagined floor they are on by counting a series of seven strings of tones. 
Elevator with distraction requires individuals to count the same pitched tones from 
the previous test while ignoring higher pitched distractor tones. This replicates the 
auditory distractions individuals hear in daily life.  
 
Executive Function 
Verbal Fluency Subtest of the Delis-Kaplan Executive Functioning System (D-KEFS) 
Verbal fluency measures an individual’s ability to produce fluent speech as well as 
‘executive’ aspects of verbal behaviour including cognitive flexibility. Assessment of 
this includes letter, category fluency with switching. Fluency tests have demonstrated 
sensitivity to acute deficits following mild-traumatic brain injury (mTBI). 
 
Hayling & Brixton Tests 
These tests include the Hayling Sentence Completion Test and the Brixton Spatial 
Anticipation Test as measures of inhibition and rule-attainment involving set shifting, 
respectively. These tests are quicker to administer and less taxing than other 
measures of executive functioning such as the Wisconsin Card Sorting Task or the 
Tower of London. The measures are normed for ages 18-80, used in a variety of 
populations both clinically and in research and demonstrate reliability and 
psychometric validity. 
 
Zoo Map Subtest of the Behavioural Assessment of Dysexecutive Syndrome (BADS) 

 
 
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The Zoo Map subtest will measure planning abilities. Participants have two attempts 
to plan a route through a zoo while adhering to sets of rules and varying amount of 
instructions. Penalties are imposed for rule breaks and lack of speed. The test 
demonstrates adequate discriminant and ecological validity. 
 
Processing Speed  
Colour Trails Test 
This test will assess processing speed as well as non-verbal aspect of sustained and 
divided attention. Participants are asked to connect digits within circles in ascending 
numerical order, beginning with 1 to 25. In Part 2, participants connect digits within 
circles with alternate colour and completion times are recorded for each trial. Adult 
version is for ages 18-89. Normative data is based on a sample of 1528 healthy 
volunteers across various ethnicities. 
 
 
CONSENT and ENROLLMENT 
 
Once a patient has indicated that they are interested in participating in MR imaging 
and analysis the research nurse or team member will contact the patient.  The research 
team member will provide them with a written and verbal explanation of the study aims 
and detail on the exact nature of the study, the implications and constraints of the 
protocol and any risks involved in taking part. It will be clearly stated that the individual 
is free to withdraw from the study at any time for any reason, without prejudice to future 
care, and with no obligation to give the reason for withdrawal. Written informed consent 
will be taken by a member of the research team trained in research consent 
procedures. This will be done face to face on the day of the study visit. Subsequent to 
this the research team member will get in contact to arrange the study visit. 
 
 
 
PARTICIPANTS: 
 
Inclusion Criteria 
• 
A patient who has been hospitalised with COVID-19 disease (with a positive 
Polymerase Chain Reaction (PCR) result for SARS-CoV2 infection) within NHS 
Grampian hospitals with subsequent subjective reporting and objective 
evidence of cognitive change.  
• 
Patients aged over 18. 
• 
Patient has completed neuropsychometric testing protocol as described above. 
• 
Participant who is willing and able to give informed consent for participation in 
the study. 
 
Exclusion Criteria 
• 
Any patient whose physical condition will preclude them from lying still for the 
duration of the brain scan. 
• 
Contraindication to magnetic resonance scanning such as an implantable 
cardiac device. 
• 
Patients who required intensive care treatment for SARS-CoV2 infection. 

 
 
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• 
Patients with a pre-existing diagnosis of a Neurodegenerative disease (eg. 
Dementia), Intellectual Disability, previous moderate/severe brain injury or 
previous brain injury with noted cognitive change. 
• 
Patients with a pre-existing neuro-inflammatory disorder (eg. Multiple 
Sclerosis).  
• 
Patients under investigation for, or with a history of, cognitive change prior to 
hospitalisation with COVID-19 disease. 
• 
Patients with a dependency on alcohol or recreational drugs. 
 
 
PROCEDURE: 
Participants who have expressed their interest to take part will be contacted by a 
member of the research team to discuss the date of their study visit, which will take 
place at the University of Aberdeen research MRI facility, Aberdeen Royal Infirmary 
Foresterhill. The potential participant will be asked about possible COVID-19 
symptoms prior to proceeding with the study visit so as to ensure robust infection 
control measures. 
 
Study visit: 
 
The patient will be asked to sign an informed consent form to enter the study. This will 
be taken on the day of the scan.   
 
Participants will be asked to complete an MRI safety questionnaire prior to the 
scanning visit and this will be checked again on the day of their study visit. They will 
be met by a researcher at the MRI facility and will be consented prior to scanning. 
The scan may involve the participant changing into some loose-fitting clothing, 
usually a set of scrubs. These will be provided for the participant on the day if 
needed.  
 
During the study visit the following will take place: 
 
Brain magnetic resonance imaging and spectroscopy 
Brain MRIs will be performed using a Philips Ingenia dStream 3T scanner. The 
protocol will include high resolution structural images (3D T1-weighted, T2-weighted, 
susceptibility weighted imaging (QSM), fluid attenuated inversion recovery (FLAIR) 
and diffusion weighted imaging (DWI/DTI)) and a resting state functional sequence. 
These sequences allow us to detect clinically significant features such as lacunes, 
extended perivascular spaces, cortical and subcortical infarct, white matter 
hyperintensities and microbleeds. The 3D T1-weighted images will allow volumetric 
analysis while FLAIR images will allow quantification of white matter hyperintensity 
lesion load and DTI will enable computation of white matter structural integrity.  
Quantitative susceptibility mapping (QSM), sensitive to iron deposition, will be 
acquired with a multi-echo gradient-echo pulse sequence. Metabolic profile will be 
quantified from spectrum acquired using single voxel Point RESolved Spectroscopy 
(PRESS) sequence from 3 targeted regions previously reported to be involved in 
cognitive decline after COVID-19. 
 
 
 
 

 
 
The ACDC study: 
Assessing Cognitive Deterioration in COVID-19 
Protocol V1  18th August 2022 
IRAS PROJECT ID: 314094 
 
 
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WITHDRAWAL PROCEDURES 
 
Participants are free to withdraw at any time during the study without having to give a 
reason.  Should this occur, additional participants will be recruited to fill in the gaps, 
but this is not expected to be a significant number. Some participants may consent to 
participate but may not wish to have a particular test done.  These patients will be 
excluded from the study. 
 
 
 
DATA COLLECTION 
 
Clinical data will be entered onto a CRF and then stored electronically on University of 
Aberdeen managed computer systems by the research team. 
 
Results from the analysis of scans/cognitive tests will be stored electronically on 
University of Aberdeen and NHS Grampian managed computer systems by the 
research team. Anonymised data will be transferred between servers, where 
necessary, using the ZendTo software facility.  
 
Data collected from participants will be stored in an anonymised fashion with the use 
of unique participant identification numbers.  Relevant data will be exported into a csv 
file and analysed using R software.  Consent forms pertaining to the study will be kept 
in a locked filing cabinet in the Aberdeen Biomedical Imaging Centre.  Data generated 
in the study will be kept for a minimum of 6 years and Dr Jonathan McLaughlin will act 
as custodian for the data.    
 
The CI and study staff involved in this project will comply with the requirements of the 
General Data Protection Regulations (GDPR) and the Data Protection Act 2018.  The 
Health Research Authority (HRA) recommended working to fulfil transparency 
requirements under the GDPR for health and care research has been included in the 
PIS. 
 
The sponsor is responsible for ensuring that trial data is archived appropriately.  
Essential data shall be retained for a period of at least 6 years following close of study. 
 
 
 
SAMPLE SIZE CALCULATION 
 
The study, envisaged as a pilot will compare n=30 patients. We will recruit from the 
Mental Health After COVID-19 Hospitalisation Team (MACH). We will work to achieve 
full data for 30 patients and the retention rate is envisaged to be high given the single 
study visit. Retention should be further bolstered in that only patients who have already 
completed neuropsychometric testing will progress forward to have the MR imaging. 
 
Power calculations: Sample size and power calculations are not possible at the pilot 
stage however our sample size of 30 will ensure a spread of measurements to allow 
us to estimate effects sizes and aid planning for future studies. 

 
 
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COMPLIANCE AND LOSS TO FOLLOW-UP 
 
In the STRADL study (Habota et al. 2019), where 1188 participants were tested, 
compliance was 90% for brain imaging, 97% for laboratory samples and 99% for 
cognitive tests. We expect similar compliance in the current study.  
 
 
POTENTIAL RISKS AND HAZARDS 
 
Magnetic resonance imaging is very safe and there are no known side effects.  The 
scan is noisy and we provide headphones to protect the participants’ ears. The study 
participant will be able to speak to the radiographer during the scan.. 
 
For female participants of child bearing age where there is a possibility of pregnancy 
there will be a requirement for a negative pregnancy test prior to undertaking the scan. 
If this is not possible the scanning will not go ahead.  
 
It is possible that an unexpected health problem could be found on the tests.  However, 
if this is the case, the participant will be notified and the results will be passed on to the 
participant’s General Practitioner (GP) and/or other relevant health professional, along 
with any recommendations for treatment that may be necessary.   
 
 
PROPOSED ANALYSES 
 
Data will be analysed using R as follows. Using the multi-echo gradient echo phase 
and magnitude data we will determine a marker of in-vivo brain iron concentration by 
Quantitative Susceptibility Mapping (QSM) (Betts et al., 2016). Cortical sub-structures 
where associations have previously been found between cognitive performance and 
iron deposition (Spence et al., 2020) will be extracted from high resolution T1-weighted 
MR scans by the FreeSurfer image analysis suite. The mean iron induced susceptibility 
(a marker of iron concentration and therefore brain inflammation) in each cortical sub-
structure will be determined. Morphological brain measures such as cortical and sub-
cortical volumes will also be extracted. A composite score will be determined from the 
cognitive tests by principal component analysis. The spectrum will be processed in 
jMRUI software for phase correction, apodisation, with spectral peak amplitude of brain 
metabolites subsequently quantified using the Advanced Method for Accurate, Robust 
and Efficient Spectral fitting of MRS data with use of prior knowledge (AMARES) 
algorithm. Associations between cognitive performance, regional iron deposition, 
volume, markers of small vessel disease and brain metabolism will be determined 
using a general linear approach while correcting for confounding variables such as age 
and BMI. 
 
 
STUDY MANAGEMENT AND OVERSIGHT ARRANGEMENTS 
 
The principal applicant and the co-applicants will supervise the MACH team 
members and Research Nurse and monitor study progress. The Research Nurse will 

 
 
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be responsible for the study log, storing/filing regulatory documents and patient 
documents as per GCP guidelines. 
 
The Research Nurse will be responsible for checking the CRFs for completeness, 
plausibility, and consistency. However, this remains the overall responsibility of the CI. 
Any queries will be resolved by the CI or delegated member of the study team.  
 
A study-specific Delegation Log will be prepared detailing the responsibilities of each 
member of staff working on the study.  
 
The study management group will consist of Study Group detailed at the start of this 
document. This group will oversee the conduct and coordination of the study. 
 
 
 
INSPECTION OF RECORDS 
 
The CI, PIs and all institutions involved in the study shall permit study related 
monitoring, audits, and REC review. The CI agrees to allow the Sponsor, or 
representatives of the Sponsor, direct access to all study records and source 
documentation. 
 
 
 
 
GOOD CLINICAL PRACTICE 
 
Ethical Conduct of the Study 
 
The study will be conducted in accordance with the principles of Good Clinical Practice 
(GCP). All staff must hold evidence of appropriate GCP training or undergo GCP 
training and this will be updated as needed throughout the study. 
 
In addition to Sponsorship approval, a favorable ethical opinion will be obtained from 
the appropriate REC and appropriate NHS R&D approval(s) will be obtained prior to 
commencement of the study. 
 
Confidentiality 
 
All results, questionnaires, reports, and other records will be identified in a manner 
designed to maintain participant confidentiality. All records will be kept in a secure 
storage area with limited access to study staff only. Clinical information will not be 
released without the written permission of the participant, except as necessary for 
monitoring and auditing by the Sponsor or its designee. The CI and study staff involved 
with this study will not disclose or use for any purpose (other than performance of the 
study) any data, record, or other unpublished, confidential information disclosed to 
those individuals for the purpose of the study. Prior written agreement from the 
Sponsor or its designee will be obtained for the disclosure of any said confidential 
information to other parties. 

 
 
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The CI and study staff involved with this study will comply with the requirements of the 
UK Data Protection Laws with regard to the collection, storage, processing and 
disclosure of personal information and will uphold the Data Protection Act’s core 
principles. The CI and study staff will also adhere, if appropriate, to the current version 
of the NHS Scotland Code of Practice on Protecting Patient Confidentiality.  Access to 
collated participant data will be restricted to the CI and appropriate study staff. 
Computers used to collate the data will have limited access measures via usernames 
and passwords. 
Published results will not contain any personal data that could allow identification of 
individual participants. 
 
 
Adverse Events 
 
An adverse event (AE) is any untoward medical event affecting a study participant. 
Each AE will be considered for severity, causality or expectedness and may be 
reclassified as a serious event or reaction based on prevailing circumstances.  
 
A serious adverse event (SAE) is any AE which; 
 
• 
Results in death 
• 
Is life threatening (i.e. the subject was at risk of death at the time of the event; 
it does not refer to an event which hypothetically might have caused death if it 
were more severe).  
• 
Requires hospitalisation or prolongation of existing hospitalisation  
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
 
All AEs and SAEs will be recorded from the time a participant consents to join the 
study until the day of completion of their scan.  
 
The Investigators will interrogate notes and other available clinical documentation, and 
sometimes question participants directly, to discern details of the occurrence of 
AEs/SAEs. If there is any doubt as to whether a clinical observation is an AE, the 
event should be recorded. 
 
This is a low-risk study and involves no interventional procedures. Only AEs and SAEs 
directly linked to the undertaking of the MR imaging protocol will be recorded. All safety 
procedures and checks around MR imaging will be implemented and adhered to. Dr 
Gordon Waiter serves as MR safety expert for NHS Grampian. 
 
In the event of an AE or SAE this will be recorded initially and then reported to the 
sponsor as per SOP UoA-NHSG-SOP-014. Follow up information will also be reported 
to the sponsor in line with the aforementioned SOP. 
 
 
INSURANCE AND INDEMNITY 
 
NHS Grampian is sponsoring the study. 
 

 
 
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Insurance: 
• 
Grampian Health Board will maintain its membership of the Clinical Negligence 
and Other Risks Insurance Scheme (“CNORIS”) which covers the legal liability 
of Grampian in relation to the study. 
 
• 
Where the study involves University of Aberdeen staff undertaking clinical 
research on NHS patients, such staff will hold honorary contracts with NHS 
Grampian Health Board which means they will have cover under NHS 
Grampian’s membership of the CNORIS scheme. 
 
Indemnity:  
The Sponsor does not provide study participants with indemnity in relation to 
participation in the Study but has insurance for legal liability as described above. 
 
 
 
STUDY CONDUCT RESPONSIBILITIES 
 
Protocol Amendments, Deviations and Breaches 
 
The CI will seek approval for any amendments to the Protocol or other study 
documents from the Sponsor, REC and NHS R&D Office(s). Amendments to the 
protocol or other study docs will not be implemented without these approvals.  
 
In the event that a CI needs to deviate from the protocol, the nature of and reasons for 
the deviation will be recorded in the CRF, documented and submitted to the Sponsor. 
If this necessitates a subsequent protocol amendment, this will be submitted to the 
Sponsor for approval and then to the appropriate REC and lead NHS R&D Office for 
review and approval.  
 
In the event that a serious breach of GCP is suspected, this will be reported to the 
Sponsor immediately using the form “Breach Report Form”.  
 
 
STUDY RECORD RETENTION 
 
Archiving of study documents will be on NHS Grampian premises in line with the 
Sponsor’s Standard Operating Procedure (SOP). At the end of the study the NHS 
Grampian archivist will be contacted to arrange appropriate archiving.   
 
END OF STUDY 
 
The end of study is defined as that point at which the final participant has undergone 
the scanning protocol. . The Sponsor and the CI have the right at any time to terminate 
the study for clinical or administrative reasons.  
The end of the study will be reported to the Sponsor and REC within 90 days, or 
15 days if the study is terminated prematurely. The CI will ensure that any appropriate 
follow up is arranged for all participants. 

 
 
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A summary report of the study will be provided to the Sponsor and REC within 1 year 
of the end of the study. 
 
 
 
 
REPORTING, PUBLICATION AND NOTIFICATION OF RESULTS 
 
Authorship Policy 
Ownership of the data arising from this study resides with the study team and their 
respective employers. On completion of the study, the study data will be analysed and 
tabulated, and a clinical study report will be prepared.  
 
Publication 
 
The clinical study report will be used for publication and presentation at scientific 
meetings.  Investigators have the right to publish orally or in writing the results of the 
study. 
 
Summaries of the results will also be made available to Investigators for dissemination 
within their clinical areas and clinics (where appropriate and according to their 
discretion). Results would also be presented at the national level to the Mental Health 
after COVID-19 Hospitalisation (MACH) national steering committee. Other forums for 
dissemination would also be envisaged including potentially to ‘Long COVID’ patient 
bodies via local and national platforms.  
 
Peer review 
 
Peer review of this protocol, and the antecedent funding application, has been sought 
from University of Aberdeen academic staff as well as NHS Grampian clinical staff. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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APPENDIX 1: References 
 
BADENOCH, J. B., RENGASAMY, E. R., WATSON, C., JANSEN, K., CHAKRABORTY, S., 
SUNDARAM, R. D., HAFEEZ, D., BURCHILL, E., SAINI, A., THOMAS, L., CROSS, 
B., HUNT, C. K., CONTI, I., RALOVSKA, S., HUSSAIN, Z., BUTLER, M., POLLAK, 
T. A., KOYCHEV, I., MICHAEL, B. D., HOLLING, H., NICHOLSON, T. R., ROGERS, 
J. P. & ROONEY, A. G. 2022. Persistent neuropsychiatric symptoms after COVID-19: a 
systematic review and meta-analysis. Brain Commun, 4, fcab297. 
 
BECKER, J. H., LIN, J. J., DOERNBERG, M., STONE, K., NAVIS, A., FESTA, J. R. & 
WISNIVESKY, J. P. 2021. Assessment of Cognitive Function in Patients After COVID-
19 Infection. JAMA network open, 4, e2130645. 
 
BETTS, M. J., ACOSTA-CABRONERO, J., CARDENAS-BLANCO, A., NESTOR, P. J. & 
DÜZEL, E. 2016. High-resolution characterisation of the aging brain using simultaneous 
quantitative susceptibility mapping (QSM) and R2* measurements at 7T. Neuroimage, 
138, 43-63. 
 
CEBAN, F., LING, S., LUI, L. M. W., LEE, Y., GILL, H., TEOPIZ, K. M., RODRIGUES, N. 
B., SUBRAMANIAPILLAI, M., DI VINCENZO, J. D., CAO, B., LIN, K., MANSUR, R. 
B., HO, R. C., ROSENBLAT, J. D., MISKOWIAK, K. W., VINBERG, M., MALETIC, 
V. & MCINTYRE, R. S. 2022. Fatigue and cognitive impairment in Post-COVID-19 
Syndrome: A systematic review and meta-analysis. Brain, behavior, and immunity, 101, 
93-135. 
 
DOUAUD, G., LEE, S., ALFARO-ALMAGRO, F., ARTHOFER, C., WANG, C., 
MCCARTHY, P., LANGE, F., ANDERSSON, J. L. R., GRIFFANTI, L., DUFF, E., 
JBABDI, S., TASCHLER, B., KEATING, P., WINKLER, A. M., COLLINS, R., 
MATTHEWS, P. M., ALLEN, N., MILLER, K. L., NICHOLS, T. E. & SMITH, S. M. 
2022. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature. 
 
HELLGREN, L., BIRBERG THORNBERG, U., SAMUELSSON, K., LEVI, R., 
DIVANOGLOU, A. & BLYSTAD, I. 2021. Brain MRI and neuropsychological findings 
at long-term follow-up after COVID-19 hospitalisation: an observational cohort study. 
BMJ Open, 11, e055164. 
 
HOSP, J. A., DRESSING, A., BLAZHENETS, G., BORMANN, T., RAU, A., 
SCHWABENLAND, M., THUROW, J., WAGNER, D., WALLER, C., NIESEN, W. D., 
FRINGS, L., URBACH, H., PRINZ, M., WEILLER, C., SCHROETER, N. & MEYER, 
P. T. 2021. Cognitive impairment and altered cerebral glucose metabolism in the subacute 
stage of COVID-19. Brain, 144, 1263-1276. 
 
RAPALINO, O., WEERASEKERA, A., MOUM, S. J., EIKERMANN-HAERTER, K., EDLOW, 
B. L., FISCHER, D., TORRADO-CARVAJAL, A., LOGGIA, M. L., MUKERJI, S. S., 

 
 
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SCHAEFER, P. W., GONZALEZ, R. G., LEV, M. H. & RATAI, E. M. 2021. Brain MR 
Spectroscopic Findings in 3 Consecutive Patients with COVID-19: Preliminary 
Observations. AJNR Am J Neuroradiol, 42, 37-41. 
 
SAMKARIA, A. & MANDAL, P. K. 2021. Brain Imaging in COVID-19. ACS Chem Neurosci, 
12, 2953-2955. 
 
SKLINDA, K., GORECKI, A., DOROBEK, M., WALECKI, J., MODRZYNSKA, A. & MRUK, 
B. 2021. Ischaemic background of brain fog in long-haul COVID-19 - a nuclear magnetic 
resonance spectroscopy-based metabonomic analysis. Preliminary results. Pol J Radiol, 
86, e654-e660. 
 
SPENCE, H., MCNEIL, C. J. & WAITER, G. D. 2020. The impact of brain iron accumulation on 
cognition: A systematic review. PLOS ONE, 15, e0240697. 
 
YESILKAYA, U. H. & BALCIOGLU, Y. H. 2020. Neuroimmune correlates of the nervous 
system involvement of COVID-19: A commentary. J Clin Neurosci, 78, 449-450. 
 
YESILKAYA, U. H., SEN, M. & BALCIOGLU, Y. H. 2021. COVID-19-related cognitive 
dysfunction may be associated with transient disruption in the DLPFC glutamatergic 
pathway. J Clin Neurosci, 87, 153-155.