Longitudinal neuroanatomical and cognitive progression of posterior cortical atrophy

Abstract

Posterior cortical atrophy is a clinico-radiological syndrome characterized by progressive decline in visual processing and atrophy of posterior brain regions. With the majority of cases attributable to Alzheimer’s disease and recent evidence for genetic risk factors specifically related to posterior cortical atrophy, the syndrome can provide important insights into selective vulnerability and phenotypic diversity. The present study describes the first major longitudinal investigation of posterior cortical atrophy disease progression. Three hundred and sixty-one individuals (117 posterior cortical atrophy, 106 typical Alzheimer’s disease, 138 controls) fulfilling consensus criteria for posterior cortical atrophy-pure and typical Alzheimer’s disease were recruited from three centres in the UK, Spain and USA. Participants underwent up to six annual assessments involving MRI scans and neuropsychological testing. We constructed longitudinal trajectories of regional brain volumes within posterior cortical atrophy and typical Alzheimer’s disease using differential equation models. We compared and contrasted the order in which regional brain volumes become abnormal within posterior cortical atrophy and typical Alzheimer’s disease using event-based models. We also examined trajectories of cognitive decline and the order in which different cognitive tests show abnormality using the same models. Temporally aligned trajectories for eight regions of interest revealed distinct (P < 0.002) patterns of progression in posterior cortical atrophy and typical Alzheimer’s disease. Patients with posterior cortical atrophy showed early occipital and parietal atrophy, with subsequent higher rates of temporal atrophy and ventricular expansion leading to tissue loss of comparable extent later. Hippocampal, entorhinal and frontal regions underwent a lower rate of change and never approached the extent of posterior cortical involvement. Patients with typical Alzheimer’s disease showed early hippocampal atrophy, with subsequent higher rates of temporal atrophy and ventricular expansion. Cognitive models showed tests sensitive to visuospatial dysfunction declined earlier in posterior cortical atrophy than typical Alzheimer’s disease whilst tests sensitive to working memory impairment declined earlier in typical Alzheimer’s disease than posterior cortical atrophy. These findings indicate that posterior cortical atrophy and typical Alzheimer’s disease have distinct sites of onset and different profiles of spatial and temporal progression. The ordering of disease events both motivates investigation of biological factors underpinning phenotypic heterogeneity, and informs the selection of measures for clinical trials in posterior cortical atrophy.

Data-driven detection of latent atrophy factors related to phenotypical variants of posterior cortical atrophy

“…8B), suggesting that individuals with prominent right-caudal atrophy tend to be in the earlier phases of clinical disease progression. These findings are in line with earlier observations that posterior cortical atrophy starts in the most posteriorly located regions of the brain and then spreads to lateral parieto-temporal cortices (Kennedy et al, 2012;Agosta et al, 2018;Firth et al, 2019), following a posterior-to-anterior pathway in line with the network-based degeneration hypothesis (Seeley et al, 2009). It may therefore be that descriptions of isolated impairments on primary visual processing and caudally located atrophy are based on individuals in an early stage of the disease, which would be in line with the observation that all posterior cortical atrophy participants show impairments in at least one primary visual domain (Lehmann et al, 2011a).…”

“…However, individuals with atrophy that predominantly affected the limbic regions also showed worse global cognition, indicating that disproportionate limbic atrophy indicates worse cognition overall. As this factor was also the only one associated with global atrophy, it seems that high limbic factor expression might be a feature of late-stage posterior cortical atrophy, which is in accordance with findings reported in previous studies Firth et al, 2019;Phillips et al, 2019).…”

“…Alzheimer's disease in the early stages of the disease Firth et al, 2019) and hypothetical models of Alzheimer's disease suggest that tau aggregation and hypometabolism precede neurodegeneration (Jack and Holtzman, 2013). This indicates that successfully identifying phenotypical variants of posterior cortical atrophy may rely on early detection using, for example, tau-PET or FDG-PET, which have already been shown to distinguish posterior cortical atrophy from typical Alzheimer's disease (Nestor et al, 2003;Whitwell et al, 2007;Rosenbloom et al, 2011;Ossenkoppele et al, 2012Ossenkoppele et al, , 2015dDay et al, 2017;Panegyres et al, 2017).…”

“…Posterior cortical atrophy is a clinical-radiological syndrome defined by progressive loss of higher-order visual functions, and atrophy that markedly affects posterior brain regions such as the parietal and occipital cortices (Benson et al, 1988;Whitwell et al, 2007;Koedam et al, 2011, Lehmann et al, 2011bCrutch et al, 2012;Alves et al, 2013, Ossenkoppele et al, 2015bFirth et al, 2019;Marinescu et al, 2019). While multiple pathologies may underlie the posterior cortical atrophy syndrome, the most common biological substrate is Alzheimer's disease, accounting for ~80% of the cases (Renner et al, 2004;Tang-Wai et al, 2004;Montembeault et al, 2018).…”

Cognitive Changes associated with Alzheimer’s disease in Down syndrome

“…The event-based model (EBM) is one such method capable of estimating orderings of multimodal measurements and staging participants 13 . The EBM has been applied previously to neuroimaging, cerebrospinal fluid (CSF), and cognitive markers in sporadic AD 14 , and more recently was reformulated to model more complex cognitive datasets in young onset AD and posterior cortical atrophy 15 .…”