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.
Highlights
Considerable heterogeneity is evident among individuals with Alzheimer’s disease both clinically (Galton et al, 2000) and pathologically (Murray et al, 2011)
A small number of cases of posterior cortical atrophy (PCA) have been attributed to alternative aetiologies including corticobasal degeneration (CBD), Lewy body disease (LBD), and prion disease (Tang-Wai et al, 2003a, b; Renner et al, 2004)
One hundred and seventeen individuals with a clinical diagnosis of PCA were recruited at three specialist centres: 100 patients at the Dementia Research Centre (DRC) at the National Hospital for Neurology and Neurosurgery London (UK), nine patients at the University Hospital Virgen del Rocio (HUVR) Memory Disorders Unit (Spain), and eight patients at the University of California San Francisco (UCSF) Memory and Aging Center (USA)
Summary
Considerable heterogeneity is evident among individuals with Alzheimer’s disease both clinically (e.g. amnesic, visual, dysexecutive/behavioural and aphasic presentations of Alzheimer’s disease) (Galton et al, 2000) and pathologically (e.g. hippocampal sparing and limbic-predominant Alzheimer’s disease subtypes accounting for 25% of cases) (Murray et al, 2011) This heterogeneity provides an important opportunity to explore the factors that promote or inhibit disease progression, both spatially and temporally. One recent example is the discovery of structural variations in amyloid-b fibrils between individuals with rapidly and slowly progressing forms of Alzheimer’s disease (Qiang et al, 2017) In this context, longitudinal quantitative tracking of variations in regional tissue damage in large cohorts of patients with different phenotypic expressions of a disease can reveal the temporal profiles of disease evolution and permit testing of the hypothesis that differentially distributed molecular lesions predict particular patterns of disease progression. Apolipoprotein E (APOE) e4 allele status alters PCA risk but with a smaller effect than for typical Alzheimer’s disease (Schott et al, 2006; Snowden et al, 2007) and an exploratory genome-wide association study has identified three candidate genetic risk factors that may be specific to PCA (Schott et al, 2016)
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