Elsevier

Neurobiology of Aging

Volume 31, Issue 8, August 2010, Pages 1275-1283
Neurobiology of Aging

Dynamic biomarkers and the pathophysiology of Alzheimer's disease
Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging

https://doi.org/10.1016/j.neurobiolaging.2010.04.007Get rights and content

Abstract

The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, a participant of the worldwide Alzheimer's Disease Neuroimaging Initiative (ADNI), performed 11C-Pittsburgh Compound B (PiB) scans in 177 healthy controls (HC), 57 mild cognitive impairment (MCI) subjects, and 53 mild Alzheimer's disease (AD) patients. High PiB binding was present in 33% of HC (49% in ApoE-ε4 carriers vs 21% in noncarriers) and increased with age, most strongly in ε4 carriers. 18% of HC aged 60-69 had high PiB binding rising to 65% in those over 80 years. Subjective memory complaint was only associated with elevated PiB binding in ε4 carriers. There was no correlation with cognition in HC or MCI. PiB binding in AD was unrelated to age, hippocampal volume or memory. Beta-amyloid (Aβ) deposition seems almost inevitable with advanced age, amyloid burden is similar at all ages in AD, and secondary factors or downstream events appear to play a more direct role than total beta amyloid burden in hippocampal atrophy and cognitive decline.

Introduction

Dementia is a leading cause of death, disability, and health expenditure in the elderly and Alzheimer's disease (AD) accounts for the majority of cases. The leading hypothesis on the cause of AD is that it results from excessive beta amyloid (Aβ) in the brain, either through increased production or impaired clearance of Aβ oligomers that then aggregate to form extracellular plaques and vascular wall deposits (Villemagne et al., 2006). However, there are many unanswered questions regarding this hypothesis including the timing and rate of Aβ deposition and its relationship to brain atrophy and cognitive decline.

Molecular neuroimaging techniques such as positron emission tomography (PET), in conjunction with related biomarkers in cerebrospinal fluid (CSF), are proving valuable in the early and differential diagnosis of AD (Fagan et al., 2006, Klunk et al., 2004, Rowe et al., 2007) and have the potential to increase our understanding of the neurobiology of AD through longitudinal observational studies of aging.

The Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship study of Aging (sometimes referred to as Australian Alzheimer's Disease Neuroimaging Initiative [ADNI]) was designed to improve the understanding of the pathogenesis of AD, focusing on its early diagnosis and the identification of factors that eventually may delay onset of AD, while also providing a cohort suitable for early intervention studies (Ellis et al., 2009). The objectives of the neuroimaging arm of AIBL were: (1) to evaluate the degree and pattern of 11C-Pittsburgh Compound B (PiB) retention in a well-characterized cohort of healthy control (HC), mild cognitive impairment (MCI), and AD participants; (2) correlate Aβ burden with clinical and cognitive measures; (3) evaluate the relation between Aβ burden and ApoE genetic status; (4) establish the prevalence of Aβ deposition in asymptomatic HC and in HC with subjective memory complaints; (5) examine the relationship of gray and white matter atrophy to Aβ deposition; and (6) prospectively evaluate the rate and pattern of Aβ deposition and brain neurodegenerative changes over time. The latter will be the subject of future papers.

The imaging protocols and aspects of the clinical and neuropsychology assessment of AIBL were designed to permit comparison and pooling of data with the ADNI allowing AIBL to be a substantial contributor to the world-wide ADNI (WW-ADNI) research effort.

Section snippets

Participants

Written informed consent was obtained from all participants. Approval for the study was obtained from the St Vincent's Hospital, Melbourne, Austin Health, Edith Cowan University and Hollywood Private Hospital Human Research Ethics Committees. Healthy controls (HC) were recruited by advertisement in the community while the MCI and AD participants were recruited from tertiary memory disorders clinics or private geriatricians, psychiatrists, and neurologists who subspecialize in dementia. The

Results

Demographic characteristics of the cohort are shown on Table 1. The MCI group was slightly, but significantly, older than the HC and AD groups. Forty-three percent of the HC group were ε4 carriers (69 heterozygous, 7 homozygous), compared with 55% of MCI (26 heterozygous, 5 homozygous), and 69% of AD (23 heterozygous, 11 homozygous). HC, MCI, and AD groups differed significantly in average MMSE scores (p < 0.05). The HC-SMC and HC-non-memory complaint (nMC) did not differ significantly in terms

Discussion

This is the first report on AIBL neuroimaging studies, where 287 participants (26% of the whole AIBL cohort) underwent MRI and PiB PET scans. Out of the 287 participants, 177 (62%) were classified as HC, 57 (20%) fulfilled criteria for MCI (90% amnestic type), and 53 (18%) fulfilled criteria for AD. The AIBL study was designed to improve understanding of the pathogenesis of AD, focusing on early AD diagnosis, while also providing a cohort suitable for early intervention studies (Ellis et al.,

Disclosure statement

All authors declare no conflicts.

Written informed consent was obtained from all participants. Approval for the study was obtained from the St Vincent's Hospital, Melbourne, Austin Health, Edith Cowan University and Hollywood Private Hospital Human Research Ethics Committees.

Acknowledgements

We thank the AIBL Study Group (www.aibl.csiro.au) and Prof. Michael Woodward, Dr. John Merory, Dr. Peter Drysdale, Ms. Tanya Betts, Dr. Rachel Mulligan, Dr. Uwe Ackermann, Dr. Gordon Chan, Dr. Kenneth Young, Dr. Sylvia Gong, Dr. Alex Bahar-Fuchs, Mr. Neil Kileen, Mr. Tim Saunder, Ms. Jessica Sagona, and Mr. Jason Bradley and for their assistance with this study.

The study was supported by the Commonwealth Scientific Industrial Research Organization (CSIRO) P-Health Flagship Collaboration Fund

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