Distinct spatiotemporal atrophy patterns in corticobasal syndrome are associated with different underlying pathologies.

Objective: To identify imaging subtypes of the cortico-basal syndrome (CBS) based solely on a data-driven assessment of MRI atrophy patterns, and investigate whether these subtypes provide information on the underlying pathology. Methods: We applied Subtype and Stage Inference (SuStaIn), a machine learning algorithm that identifies groups of individuals with distinct biomarker progression patterns, to a large cohort of 135 CBS cases (52 had a pathological or biomarker defined diagnosis) and 252 controls. The model was fit using volumetric features extracted from baseline T1-weighted MRI scans and validated using follow-up MRI. We compared the clinical phenotypes of each subtype and investigated whether there were differences in associated pathology between the subtypes. Results: SuStaIn identified two subtypes with distinct sequences of atrophy progression; four-repeat-tauopathy confirmed cases were most commonly assigned to the Subcortical subtype (83% of CBS-PSP and 75% of CBS-CBD), while CBS-AD was most commonly assigned to the Fronto-parieto-occipital subtype (81% of CBS-AD). Subtype assignment was stable at follow-up (98% of cases), and individuals consistently progressed to higher stages (100% stayed at the same stage or progressed), supporting the model's ability to stage progression. Interpretation: By jointly modelling disease stage and subtype, we provide data-driven evidence for at least two distinct and longitudinally stable spatiotemporal subtypes of atrophy in CBS that are associated with different underlying pathologies. In the absence of sensitive and specific biomarkers, accurately subtyping and staging individuals with CBS at baseline has important implications for screening on entry into clinical trials, as well as for tracking disease progression.

The contribution of apolipoprotein E alleles on cognitive performance and dynamic neural activity over six decades.

Neuroimaging shows brain-functional differences due to apolipoprotein E (APOE) polymorphisms may exist decades before the increased risk period for Alzheimer's disease, but little is known about their effect on cognition and brain function in children and young adults. This study assessed 415 healthy epsilon2 and epsilon4 carriers and matched epsilon3/epsilon3 controls, spanning ages 6-65, on a range of cognitive tests. Subjects were also compared on a new dynamical measure of EEG activity during a visual working memory task using alphabetical stimuli. epsilon4 subjects had better verbal fluency compared to epsilon3, an effect that was strongest in 51-65 year-olds. No epsilon4 deficits in cognition were found. In 6-15 year-olds, there were differences in total spatio-temporal wave activity between epsilon3 and epsilon4 subjects in the theta band, approximately 200ms post-stimulus. Differences in brain function in younger epsilon4 subjects and superior verbal fluency across the entire age range suggest that the APOE epsilon4 allele is an example of antagonistic pleiotropy.