Automated mapping of hippocampal atrophy in 1-year repeat MRI data from 490 subjects with Alzheimer's disease, mild cognitive impairment, and elderly controls

Abstract

As one of the earliest structures to degenerate in Alzheimer's disease (AD), the hippocampus is the target of many studies of factors that influence rates of brain degeneration in the elderly. In one of the largest brain mapping studies to date, we mapped the 3D profile of hippocampal degeneration over time in 490 subjects scanned twice with brain MRI over a 1-year interval (980 scans). We examined baseline and 1-year follow-up scans of 97 AD subjects (49 males/48 females), 148 healthy control subjects (75 males/73 females), and 245 subjects with mild cognitive impairment (MCI; 160 males/85 females). We used our previously validated automated segmentation method, based on AdaBoost, to create 3D hippocampal surface models in all 980 scans. Hippocampal volume loss rates increased with worsening diagnosis (normal=0.66%/year; MCI=3.12%/year; AD=5.59%/year), and correlated with both baseline and interval changes in Mini-Mental State Examination (MMSE) scores and global and sum-of-boxes Clinical Dementia Rating scale (CDR) scores. Surface-based statistical maps visualized a selective profile of ongoing atrophy in all three diagnostic groups. Healthy controls carrying the ApoE4 gene atrophied faster than non-carriers, while more educated controls atrophied more slowly; converters from MCI to AD showed faster atrophy than non-converters. Hippocampal loss rates can be rapidly mapped, and they track cognitive decline closely enough to be used as surrogate markers of Alzheimer's disease in drug trials. They also reveal genetically greater atrophy in cognitively intact subjects.

Genetic Risk Factors of Imaging Measures Associated with Late-Onset Alzheimer’s Disease

“…In line with the strong and consistent results for APOE when using LOAD as the phenotype, most T-1 weighted MRI studies reported an association of APOE e4 with accelerated LOAD-related volume loss in the hippocampal region. [53][54][55][56] This is supported by several studies exploring the effect of the APOE e4 allele on glucose metabolism using FDG-PET, [57][58][59][60] or amyloid deposition using ([¹¹C] PiB-PET. [61][62][63] Few studies have examined the association between other genes and LOAD imaging measures, and most of these were GWAS studies.…”

Structural imaging markers for therapeutic trials in Alzheimer's disease

“…This contrasts with the rates of only 1-2% per year in normal subjects (aged around 70-80 years) (9,10,11). This disease-related difference offers a potential measure which can be used to provide evidence for disease modification.…”

“…Most trials have used manual outlining of the hippocampus; more recently semi-automated measures have been used -some of these require landmarks to be placed around the hippocampus from which an algorithm delineates the hippocampal boundaries. Fully automated (template-based) measures have also been developed but have not to date been used in large trials (3,10).…”

“…The development of software that can provide automated or semi-automated measurements of region volumes or cortical thickness, has led to these measures being suggested as outcomes in disease modification trials (3,4,10). Multiple regions may be measured which avoids the limitations of one global or regional measure, nonetheless this raises issues for trial designs that typically pre-specify a single outcome and may require a step-down approach to several measures.…”

Brain Structure and Obesity

“…Further, patients with AD have abnormally high rates of brain atrophy [Apostolova et al, 2006;Callen et al, 2001;Leow et al, 2009]. Additionally, brain atrophy may be detectable on MRI even before cognitive impairment is clinically evident, as demonstrated in a study showing greater atrophy in asymptomatic APOE4 carriers compared to non-carriers [Morra et al, 2009]. …”