title: Cholinergic subcortical hyperintensities in Alzheimer's disease patients from the Sunnybrook Dementia Study: relationships with cognitive dysfunction and hippocampal atrophy.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: LC Campbell Cognitive Neurology Research Unit, Sunnybrook Heath Sciences Centre, Toronto, Canada Heart & Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, Toronto, Canada Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Canada.
authors.forename: Alicia A
authors.initials: AA
authors.lastname: McNeely
authors.affiliation: LC Campbell Cognitive Neurology Research Unit, Sunnybrook Heath Sciences Centre, Toronto, Canada Heart & Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, Toronto, Canada Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Canada.
authors.forename: Joel
authors.initials: J
authors.lastname: Ramirez
authors.affiliation: LC Campbell Cognitive Neurology Research Unit, Sunnybrook Heath Sciences Centre, Toronto, Canada Heart & Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, Toronto, Canada Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Canada University of Toronto, Institute of Medical Science, Department of Medicine (Neurology), Toronto, Canada.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Nestor
authors.affiliation: LC Campbell Cognitive Neurology Research Unit, Sunnybrook Heath Sciences Centre, Toronto, Canada Heart & Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, Toronto, Canada Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Canada.
authors.forename: Jiali
authors.initials: J
authors.lastname: Zhao
authors.affiliation: LC Campbell Cognitive Neurology Research Unit, Sunnybrook Heath Sciences Centre, Toronto, Canada Heart & Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, Toronto, Canada Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Canada.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Research Design and Biostatistics, Sunnybrook Heath Sciences Centre, Toronto, Canada.
authors.forename: Alex
authors.initials: A
authors.lastname: Kiss
authors.affiliation: Ontario Brain Institute, Toronto, Canada Rotman Research Institute of Baycrest, Toronto, Canada.
authors.forename: Donald T
authors.initials: DT
authors.lastname: Stuss
authors.affiliation: LC Campbell Cognitive Neurology Research Unit, Sunnybrook Heath Sciences Centre, Toronto, Canada Heart & Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, Toronto, Canada Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Canada University of Toronto, Institute of Medical Science, Department of Medicine (Neurology), Toronto, Canada.
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Black
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology* / Q000523:psychology*; D001284:Atrophy / Q000473:pathology / Q000523:psychology; D002799:Cholinergic Fibers / Q000473:pathology*; D003071:Cognition / Q000502:physiology*; D056344:Executive Function / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008568:Memory / Q000502:physiology; D008875:Middle Aged; D009483:Neuropsychological Tests
keywords: Alzheimer's disease; cholinergic pathway; hippocampus; magnetic resonance imaging; memory; small vessel disease; subcortical hyperintensity