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

Article type: Research Article

Authors: McNeely, Alicia A.^{a; b; c; 1} | Ramirez, Joel^{a; b; c; *; 1} | Nestor, Sean M.^{a; b; c; e} | Zhao, Jiali^{a; b; c} | Gao, Fuqiang^{a; b; c} | Kiss, Alex^d | Stuss, Donald T.^{f; g} | Black, Sandra E.^{a; b; c; e}

Affiliations: [a] LC Campbell Cognitive Neurology Research Unit, Sunnybrook Heath Sciences Centre, Toronto, Canada | [b] Heart & Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, Toronto, Canada | [c] Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Canada | [d] Department of Research Design and Biostatistics, Sunnybrook Heath Sciences Centre, Toronto, Canada | [e] University of Toronto, Institute of Medical Science, Department of Medicine (Neurology), Toronto, Canada | [f] Ontario Brain Institute, Toronto, Canada | [g] Rotman Research Institute of Baycrest, Toronto, Canada

Correspondence: [*] 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.

Note: [1] These authors contributed equally to this work.

Abstract: 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, 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.

Keywords: Alzheimer's disease, cholinergic pathway, hippocampus, magnetic resonance imaging, memory, small vessel disease, subcortical hyperintensity

DOI: 10.3233/JAD-140588

Journal: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 785-796, 2015