Detection of cognitive deficits years prior to clinical diagnosis across neurological conditions
Authors: Tai Xin You , Toniolo Sofia , Llewellyn David , van Duin Cornelia M. , Husain Masud , Manohar Sanjay 
Published: July 2024

AbstractImportanceUnderstanding the cognitive trajectory of a neurological disease can provide important insight on underlying mechanisms and disease progression. Cognitive impairment is now well established as beginning many years before the diagnosis of Alzheimer’s disease, but pre-diagnostic profiles are unclear for other neurological conditions that may be associated with cognitive impairment.ObjectiveCompare pre-diagnostic and post-diagnostic cognition and global brain volume in ischaemic stroke, focal epilepsy, Parkinson’s disease, multiple sclerosis, motor neurone disease (amyotrophic lateral sclerosis) and migraine using time-to-diagnosis and time-from-diagnosis data in relation to time of assessment.DesignAnalysis the prospective UK Biobank cohort with study baseline assessment performed between 2006-2010 and participants followed until 2021.SettingMulticenter, population-based study.ParticipantsSample of 497,252 participants, aged between 38 and 72 years, at baseline with an imaging sub-sample of 42,468 participants.ExposureParticipants with each neurological condition were compared to a healthy control group.Main outcomes and measuresA continuous measure of executive function and magnetic resonance imaging brain measures of total grey matter and hippocampal volume.ResultsOf the 497,252 participants (226,206 [45.5%] men, mean [SD] age, 57.5[8.1] years), 12,755 had ischaemic stroke, 6,758 had a diagnosis of focal epilepsy, 3,315 had Parkinson’s disease, 2,315 had multiple sclerosis, 559 had motor neurone disease and 18,254 had migraine either at study baseline or diagnosed during the follow-up period. Apart from motor neurone disease, all conditions had lowerpre-diagnosisexecutive function compared to controls (assessment performed median 7.4 years before diagnosis). Participants with focal epilepsy and multiple sclerosis showed a gradual worsening in executive function up to 15 years prior to diagnosis, while ischaemic stroke was characterised by a modest decline for a few years followed by a substantial reduction at the time of diagnosis. By contrast, participants with migraine showed improved post-diagnosis cognitive scores. Pre-diagnosis MRI grey matter volume was lower than controls for stroke, Parkinson’s disease and multiple sclerosis (scans performed median 1.7 years before diagnosis), while other conditions had lower volumes post-diagnosis.ConclusionThese cognitive trajectory models reveal disease-specific temporal patterns, including a long cognitive prodrome associated with focal epilepsy and multiple sclerosis. The findings may help to prioritise risk management of individual diseases and inform clinical decision-making.Key PointsQuestionWhat is the pre-diagnosis cognitive profile across neurological conditions of ischaemic stroke, focal epilepsy, Parkinson’s disease, multiple sclerosis, motor neurone disease and migraine?FindingsThis cohort study of 495 149 participants, aged between 38 and 72 years, identified gradual worsening of cognition up to 15 years prior to clinical diagnosis in participants with focal epilepsy and multiple sclerosis while stroke was associated with a modest decline for a few years followed by a substantial reduction at the time of diagnosis. Migraine was associated with post-diagnosis improvement in cognitive scores.MeaningCognitive trajectory models identify disease-specific temporal patterns that may help to prioritise risk management of individual diseases and inform clinical decision-making.