IN VIVO IMAGING OF BASAL FOREBRAIN ATROPHY: A POTENTIAL IMAGING MARKER OF PREDEMENTIA ALZHEIMER'S DISEASE

Abstract

Background: Alzheimer’s disease (AD) is characterized by a selective loss of cholinergic neurons in the basal forebrain cholinergic system (BFCS).We used stereotactic cytoarchitectonic maps with multimodal imaging to investigate the onset and temporal dynamics of BFCS degeneration in predementia and dementia stages of AD, its association with cortical amyloid accumulation and its potential use as diagnostic biomarker of AD. Methods: We assessed volumetric changes in the BFCS in a large number (N>800) of subjects, including AD patients, subjects with Mild Cognitive Impairment (MCI), predementia AD (CSF-positive MC) as well as cognitively normal controls. Volumetric measures of the BFCS were evaluated for their diagnostic utility in predementia and clinically manifest stages of AD. Using AV45and FDG-PET scans from the ADNI2 database, we assessed associations between BFCS degeneration and cortical changes in amyloid deposition and hypometabolism, respectively, in the prodromal phase of AD. In a multicentre study, we determined the stability of BFCS volumetry for the detection of predementia stages of AD across 10 different scanners. Results: The findings suggest that BFCS volume is particularly vulnerable to degeneration in advanced age and the presence of prodromal AD has an additional effect on BFCS volume loss. In clinically manifest stages of AD the diagnostic accuracy of BFCS volume is comparable to that of hippocampus volume. However, subregional volume of the posterior BFCS is more accurate than hippocampus volume in the detection of predementia AD compared to healthy controls, both in single and multicentre settings. In addition, in the predementia phase of AD BFCS volume is significantly associated with AV45-PET measured cortical amyloid deposition, suggesting a high specificity for AD pathology in predementia subjects. BFCS atrophy correlates with performance decline in tests of both memory and attention/executive function in MCI. Regression analyses in FDG-PET scans indicate that the differential effect of BFCS atrophy on cognitive function is mediated by its association with hypometabolism in distinct cortical networks underlying these specific cognitive functions. Conclusions: In-vivo BFCS enables the assessment of BFCS changes in predementia AD, and determining the temporal dynamics of atrophic changes and their association with cortical amyloid deposition.