Remote Digital Cognitive Assessment Reveals Cognitive Deficits Related to Hippocampal Atrophy in Autoimmune Limbic Encephalitis

Autoimmune Limbic Encephalitis (ALE) is a neurological disease characterised by inflammation of the limbic regions of the brain, mediated by pathogenic autoantibodies. Because cognitive deficits persist following acute treatment of ALE, the accurate assessment of long-term cognitive outcomes is important for clinical assessments and trials. However, evaluating cognition is costly and an unmet need for validated digital methods exists. We investigated whether remote digital methods could identify previously characterised cognitive impairments in ALE patients and would correlate with standard neuropsychological assessment and hippocampal volume. The cognitive performance of 21 chronic ALE patients along with 54 age-matched healthy controls was assessed with a battery of 12 cognitive tasks from the Cognitron online platform. ALE patients performed significantly worse in memory, visuospatial abilities, executive function, and language. No impairments in digit & spatial span, target detection (attention) and emotion discrimination were observed. The global score on the online cognitive tasks correlated significantly with the established Addenbrooke’s Cognitive Examination III (ACE) pen-and-paper test. Deficits in visuospatial processing and language were identified in ALE compared to controls using remote digital testing but not the ACE, highlighting higher sensitivity of computerised testing to residual cognitive impairment. Finally, the hippocampal volume of ALE patients and healthy controls correlated with online cognitive scores. Overall, these findings demonstrate that remote, online testing may facilitate the characterisation of cognitive profiles in complex neurological diseases. ### Competing Interest Statement A.H. and P.J.H. are co-directors and owners of H2 Cognitive Designs Ltd. A.H. is director and owner of Future Cognition Ltd, which supports online cognitive studies and develops custom cognitive assessment software respectively. S.R.I. has received honoraria/research support from UCB, Immunovant, MedImmun, Roche, Janssen, Cerebral therapeutics, ADC therapeutics, Brain, CSL Behring, and ONO Pharma and receives licensed royalties on patent application WO/2010/046716 entitled 'Neurological Autoimmune Disorders' and has filed two other patents entitled "Diagnostic method and therapy" (WO2019211633 and US-2021-0071249-A1; PCT application WO202189788A1) and "Biomarkers" (PCT/GB2022/050614 and WO202189788A1). No other author declares competing interests. ### Funding Statement This work was funded by Wellcome Trust Principal Research Fellowship to M.H., Medical Research Council CSF [MR/P00878X] and National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) to S.G.M. and in part by a senior clinical fellowship from the Medical Research Council [MR/V007173/1], Wellcome Trust Fellowship [104079/Z/14/Z], and by the NIHR Oxford BRC to S.R.I. Additional funding by the Berrow Foundation to K.S. and the Rhodes Scholarship to B.A. supported this work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study received ethical approval from Oxford University's Ethics Committee (18/SC/0048 & REC16/YH/0013). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.