Cholinergic Subcortical Hyperintensities in Alzheimer's Disease Patients from the Sunnybrook Dementia Study: Relationships with Cognitive Dysfunction and Hippocampal Atrophy

Background: Subcortical hyperintensities within the cholinergic fiber projections (chSH) on MRI are believed to reflect cerebral small vessel disease (SVD) which may adversely impact cognition. Additionally, hippocampal atrophy represents a commonly used biomarker to support the diagnosis of Alzheimer’s disease (AD). Objective: To examine potential differences in neuropsychological test performance between AD patients (n= 234) with high and low chSH volumes and whether these differences corresponded to hippocampal atrophy. Methods: A modified version of Lesion Explorer was used to volumetrically quantify chSH severity. The Sunnybrook Hippocampal Volumetry Tool was applied to obtain hippocampal volumes. Composite z-scores to assess executive, memory, and visuospatial functioning were generated from standardized neuropsychological test performance scores. Results: Inter-method technique validation demonstrated a high degree of correspondence with the Cholinergic Pathways Hyperintensities Scale (n= 40, ρ = 0.84, p< 0.001). After adjusting for brain atrophy, disease severity, global SH volumes, 1These authors contributed equally to this work. ∗Correspondence to: Joel Ramirez, LC Campbell Cognitive Neurology Research Unit, 2075 Bayview Avenue, Rm A4 21, Toronto, Ontario, M4N 3M5, Canada. Tel.: +416 480 6100 x 3225; E-mail: joelr@sri.utoronto.ca. ISSN 1387-2877/15/$27.50 © 2015 – IOS Press and the authors. All rights reserved 786 A.A. McNeely et al. / Cholinergic Subcortical Hyperintensity in AD and demographic variables, multivariate analyses revealed a significant group difference, with the high chSH group demonstrating poorer memory function compared to the low chSH group (p= 0.03). A significant difference was found between low and high chSH groups in total (p< 0.05) and left (p< 0.01) hippocampal volume. Conclusion: These results suggest degradation of the cholinergic projections due to strategic SVD may independently contribute to memory dysfunction and hippocampal atrophy. Future studies examining subcortical vasculopathy in the cholinergic pathways may have implications on the development of therapeutic strategies for dementia and SVD.