Mapping the multidimensional geometric landscape of graded phenotypic variation and progression in neurodegenerative syndromes

Abstract

Clinical variants of Alzheimers disease (AD) and frontotemporal lobar degeneration (FTLD) display a spectrum of cognitive-behavioural changes varying between individuals and over time. Understanding the landscape of these graded individual-/group-level longitudinal variations is critical for precise phenotyping; however, this remains challenging to model. Addressing this challenge, we leverage the National Alzheimers Coordinating Center database to derive a unified geometric framework of graded AD/FTLD longitudinal phenotypic variation. Using three time-point, cognitive-behavioural and clinical data from 390 typical, atypical and intermediate AD/FTLD variants, we apply advanced data-science approaches to derive low-dimensional geometric spaces capturing core features underpinning AD/FTLD clinical progression. Importantly, these geometries enable the assimilation and inter-relation of paradigmatic and mixed cases, capturing dynamic individual trajectories, and linking syndromic variability to neuropathology and key clinical end-points such as survival. This resultant mapping of dynamics underlying cognitive-behavioural evolution potentially holds paradigm-changing implications to predicting phenotypic diversification and phenotype-neurobiological mapping in AD/FTLD.

Symptom‐based staging for logopenic variant primary progressive aphasia

“…Our findings corroborate recent formulations of lvPPA as a multidimensional AD phenotype within the wider syndromic spectrum of AD, grounded in shared neural network anatomy [19][20][21][22]. Syndromic phenotypes converge with disease progression: for example, a language profile similar to lvPPA develops in posterior cortical atrophy [2], the AD-linked communication phenotype evolving at different rates across syndromes.…”

Social-semantic knowledge in frontotemporal dementia and after anterior temporal lobe resection

“…Second, recent large-scale studies have utilised a transdiagnostic approach and applied datadriven analyses to reveal the shared clinical, cognitive and behavioural dimensions in FTD and their neurobiological mechanisms. 1,9,86,98,103 This has key implications for the development of symptomatic treatments, which could target specific cognitive/behavioural dimensions that span across FTD syndromes (and potentially other neurological disorders) and stratify patients for symptomatic trials based on the presence/absence of a dimension regardless of the diagnostic label or neuropathology. Furthermore, it may be possible to titrate interventions based on an individual patient's position across these dimensions.…”