Graded multidimensional clinical and radiological variation in patients with Alzheimer’s disease and posterior cortical atrophy

Abstract Background and ObjectivesAlzheimer’s disease spans heterogeneous typical and atypical phenotypes. Posterior cortical atrophy is one striking example, characterised by prominent impairment in visual and other posterior functions in contrast to typical, amnestic Alzheimer’s disease. The primary study objective was to establish how the similarities and differences of cognition and brain volumes within Alzheimer’s disease and posterior cortical atrophy (and by extension other Alzheimer’s disease variants), can be conceptualised as systematic variations across a transdiagnostic, graded multidimensional space. MethodsThis was a cross-sectional, single-center, observational, cohort study performed at the National Hospital for Neurology & Neurosurgery, London, UK. Data were collected from a cohort of PCA and AD patients, matched for age, disease duration and MMSE scores. There were two sets of outcome measures: (1) scores on a neuropsychological battery containing 22 tests spanning visuoperceptual and visuospatial processing, episodic memory, language, executive functions, calculation, and visuospatial processing; and (2) measures extracted from high-resolution T1-weighted volumetric MRI scans. Principal component analysis was used to extract the transdiagnostic dimensions of phenotypical variation from the detailed neuropsychological data. Voxel-based morphometry was used to examine associations between the PCA-derived clinical phenotypes and the structural measures. ResultsWe enrolled 93 PCA participants (mean: age = 59.9 yrs, MMSE = 21.2; 59/93 female) and 58 AD participants (mean: age = 57.1 yrs, MMSE = 19.7; 22/58 female). The principal component analysis for posterior cortical atrophy (sample adequacy confirmed: Kaiser-Meyer-Olkin = 0.865) extracted three dimensions accounting for 61.0% of variance in patients’ performance, reflecting general cognitive impairment, visuoperceptual deficits and visuospatial impairments. Plotting Alzheimer’s disease cases into the posterior cortical atrophy-derived multidimensional space, and vice versa, revealed graded, overlapping variations between cases along these dimensions, with no evidence for categorical-like patient clustering. Likewise, the relationship between brain volumes and scores on the extracted dimensions was overlapping for posterior cortical atrophy and Alzheimer’s disease cases. DiscussionThese results provide evidence supporting a reconceptualization of clinical and radiological variation in these heterogenous Alzheimer’s disease phenotypes as being along shared phenotypic continua spanning posterior cortical atrophy and Alzheimer’s disease, arising from systematic graded variations within a transdiagnostic, multidimensional neurocognitive geometry.