In a recent study posted to the medRxiv preprint* server, researchers evaluated the use of the Oxford Cognitive Testing Portal's (OCTAL) digital cognitive testing platform for Alzheimer's disease (AD) patients and correlated their findings with serological biomarkers of AD.
AD research faces a significant limitation in measuring cognitive performance robustly, remotely, and frequently. There are no established online digital platforms validated against serological biomarkers of AD. Digital metrics obtained using computerized tests can detect subtle signs of impairment that cannot be captured by standard tests of cognition. These measures could be valuable tools in the early phases of the disease when cognitive impairment is at subthreshold levels on commonly used clinical scales. Additionally, they could track disease progression more sensitively.
Study: Digital cognitive test performance and relationship to plasma biomarkers in Alzheimer’s disease. Image Credit: PopTika / Shutterstock
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
About the study
In the present study, researchers determined the association between digital online cognitive metrics and serological biomarker levels among AD patients.
A novel online platform was used to assess cognitive functions in 46 Alzheimer's disease (AD) patients and 53 elderly healthy controls (EHC1). Serological biomarkers of AD such as beta-amyloid (Aβ)42/Aβ 40 ratio, phosphorylated tau181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were also measured. The participants' performance was compared to a larger sample of 256 elderly control adults (EHC2) over the age of 50 who were recruited using the Prolific participant recruitment platform.
Among Alzheimer's disease (AD) patients, digital cognitive testing was used to assess visual short-term memory (VSTM), visuospatial copying, long-term memory (LTM), processing speed, and executive function. The Object-in-Scene Memory Task (OIS), Trail Making Test (TMT), Oxford Memory Test (OMT), a drag-and-drop version of the Rey-Osterrieth Complex Figure (ROCF), Freestyle Corsi Block Task (CORSI), and Digit Symbol Substitution Test (DSST) were among the challenges.
Participants completed mood and motivation-related questionnaires [including the Apathy Motivation Index (AMI) and the Geriatric Depression Scale (GDS)], as well as serum collection, in-person neuropsychological assessment, and web-based digital cognitive testing. Using the 2018 criteria, AD dementia patients were classified as having the clinical syndrome of AD.
All research participants were UK citizens who spoke English fluently, had normal or corrected-to-normal visual acuity, no color blindness, and self-reported neurological health. Individuals in the elderly healthy control group were above the age of 50, did not have neurological or mental disorders, did not take psychoactive drugs, and scored over the normalcy criterion [88 out of 100 total Addenbrooke's Cognitive Examination-III (ACE) score]. In total, 40 individuals who failed attention tests were eliminated from the study.
Results
As compared to the EHC1 group, Alzheimer's disease patients showed significant impairments in all online cognitive assessments, with large effect sizes and performance correlating with serological biomarkers, particularly pTau181. AD patients had a significant loss in executive functioning, as measured by TMT and DSST, with an average of 8.50 standard deviations (SDs) below expectation.
In the OMT, CORSI, LTM, and OIS tests, AD patients performed 2.0 to 7.5 standard deviations below expectations in recognizing and localizing recalled things. The OIS and ROCF tests revealed that individuals with AD were notably weak in memory recall. EHCs remembered 80.0% of ROCF task components rapidly, whereas AD patients scored below 50.0% (i.e., 5.20 standard deviations below expectation). In numerous cognitive parameters, the EHC2 group performed modestly but considerably better than the EHC1 group. The OMT test was especially difficult for online EHC2 participants.
Compared to controls, AD patients showed greater mean values for serological NfL, GFAP, and pTau181 levels and lower values for the Aβ42/ Aβ40 ratio. In comparison to EHCs, Alzheimer's disease patients were more depressed and apathetic. The total degree of apathy was considerably associated with the extent of depression in all subjects, although it showed non-significant correlations with the online cognitive indicators. The Aβ42/ Aβ40 ratio had the least correlation with cognitive ability and the other serological indicators. ROCF and OIS were the digital cognitive indicators most closely related to serum biomarkers. The tests having the poorest associations with serological biomarkers were OMT and TMT.
The NfL, GFAP, and pTau181 levels were linked with many STM indicators; better cognitive performance was associated with lower levels of serological biomarkers. Likewise, the serological levels were linked to executive function measurements, including TMT and DSST, as well as visuospatial abilities, as measured using ROCF scores. The Aβ42:40 ratio was related to ROCF instant recall scores. The pTau181 marker was linked to many measures, whereas GFAP was linked to guessing and misbinding rates, and the neurofilament light chain levels were linked to response imprecision.
As compared to all serological markers, two measures of visual memory, ROCF recall and immediate object accuracy on the OIS task, performed best and were stronger predictors of group categorization (Alzheimer's disease or controls). Furthermore, except for pTau181, performance on the TMT, CORSI, DSST, and OMT predicted groups was superior to all serological indicators. The model combining pTau181, ROCF recall, and OIS immediate object accuracy component with an area under the curve (AUC) value of 1.0 achieved complete separation of AD patients from controls when employed in combination.
Overall, the study findings showed that AD patients can benefit from online cognitive testing to measure their cognitive function and relate it to serological biomarker levels. Digital cognitive metric testing showed impaired performance in AD patients, with serological pTau181 being the most closely correlated with cognitive metrics. The use of online evaluations could transform screening, recruitment, and stratification into clinical trials and longitudinal follow-up in intervention studies.
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Plasma pTau181 predicts Alzheimer’s progression in real-world memory clinic patients