Aims and objectives
Develop an adaptive, scalable, self-administered, digital comprehensive cognitive
screening tool to detect cognitive impairments in patients with cerebrovascular disease.
The IC3 will:
I. Detect both domain-general (e.g. executive function) and domain-specific (e.g.
aphasia, apraxia, neglect) deficits post-stroke.
II. Allow monitoring to occur at scale, in a cost-efficient manner, as test
administration can occur independent of trained professionals.
III. Minimise the effects of neglect or aphasia on cognitive assessments. IV. Have high
test-re-test reliability for repeated-testing longitudinally.
Validate the IC3 against commonly used cognitive screening tools.
Apply the IC3 in a cohort of stroke survivors, as part of the main study, to map their
trajectory of cognitive impairment over the course of the first year after stroke.
Identify novel biomarkers of cognitive outcome (cognitive scores at 1 year) and recovery
trajectory through the main study using:
I. Premorbid demographics, and comorbid physical, neuropsychological and socioeconomic
factors II. Structural and functional MRI brain imaging, to assess metrics of cerebrovascular
disease load, stroke lesion topology and brain network dynamics.
III. Blood biomarkers of neurodegeneration (total microtubule-associated protein TAU;
Phosphorylated TAU isoforms; Amyloid Aβ42/40 ratio) and neuroaxonal injury (Neurofilament
Light - NFL; Glial Fibrillary Acidic protein - GFAP). The study will characterise the time
course of the blood biomarkers over the first year after acute stroke and relate these to MRI
measures of axonal injury and brain atrophy, as well as cognitive and functional outcomes at
12 months.
IC3 Assessment Design and Development
Cognitive tests. The IC3 assessment covers 22 short tasks, spanning a wide range of cognitive
domains followed by several clinically-validated questionnaires, designed to be completed in
under 60-70 minutes. IC3 is available via a web-browser on any modern device (smartphone,
tablet, computer/laptop). To launch the assessment, the participant clicks on a link created
by the study team.
The digital nature of the IC3 affords scalability in cognitive monitoring by being usable in
both the clinical setting and home environment in the absence of a trained clinician. As well
as reducing healthcare costs, this feature promotes accessibility of the assessment for
physically disabled patients in whom attendance to healthcare or research setting is
difficult. Compared to pen and paper tests, the IC3 test administration is standardised,
scoring is automated and more detailed response metrics per individual tests are collected
(e.g. capturing reaction time and trial-by-trial variability in responses, as well as
accuracy). This allows real-time evaluation of cognitive impairments against normative
samples of age-, education- and sex- matched controls.
Demographic and neuropsychiatric questionnaires. A number of health questionnaires and
modified versions of relevant clinically-validated questionnaires are completed by the
patient or carers to assess mood, apathy, fatigue and sleep.
At the end of the assessment the participant will be given a graphical, easy-to-understand
diagram that highlights their performance against normative data. The normative data will be
based on single time-point data collected remotely from large sample of healthy controls
(>3000).
Main IC3 study design
This prospective observational longitudinal study aims to recruit 300 patients with acute
stroke and obtain repeated measures of cognition and psychosocial status at baseline,
3-months, 6-months and 12-months post ictus. IC3 is currently a single-site study at Imperial
College Healthcare NHS Trust, England, and commenced recruitment in 2022. In addition to the
cognitive monitoring, all patients will be invited to take part in MRI brain imaging and
blood biomarker sub-studies.
IC3 validation sub-study. A minimum of 100 patients will undergo clinically validated pen and
paper cognitive screens. Test-retest reliability analyses will estimate the impact of
learning effects on performance, and compare remote administration with in-person delivery of
the assessment.
MRI sub-study. Clinically acquired brain imaging at the time of the acute stroke (including
FLAIR and DWI sequences) will be obtained. All 300 patients will be invited to undergo
additional brain MRI imaging at 3 and 12 months using a Siemens Verio 3T scanner at the
Imperial College Clinical Imaging Facility. MRI measures will be used as prognostic
indicators for cognitive trajectory.
Blood biomarkers sub-study. Blood samples will be obtained at baseline, and at 3, 6 and 12
months from 200 patients. Two EDTA (plasma) and two SST (serum) samples will be collected.
Sample processing involves centrifugation at 2000g for 10 minutes at 4°C, followed by secure
storage at -80°C. Additional single PAXgene sample will be collected at one time point for
DNA storage for future analysis. The primary plasma biomarker of interest will be NFL.
Additional markers including GFAP, total TAU, phosphorylated TAU and Amyloid Aβ42/40 ratio
will be quantified. Testing will be performed at University College London via a digital
ELISA technique, using a Quanterix Simoa analyser to provide ultrasensitive assessment of
concentrations.
Study Population
Participant identification, recruitment and consent. Patients will be recruited from the
Imperial College Healthcare NHS Trust by study personnel and the clinical team. Our goal is
to recruit patients as early after stroke as is practical, and ideally within ten days to
facilitate acute blood biomarker assessment. Those satisfying the inclusion and exclusion
criteria will be approached and consented. If a patient is unable to provide fully informed
consent, for example due to severe aphasia, we will assent with permission from a consultee.
Patients that have been assented will be reconsented if they are subsequently able to provide
full informed consent. The consent procedure will be carried out in strict compliance with
national legislation and General Data Protection Regulation. Control participants will be
aged > 18 and without history of neurological illness or serious psychiatric illness.