Twelve-month metabolic declines in probable Alzheimer's disease and amnestic mild cognitive impairment assessed using an empirically pre-defined statistical region-of-interest: Findings from the Alzheimer's Disease Neuroimaging Initiative
Introduction
Alzheimer's disease (AD) is the most common form of disabling cognitive impairment in older adults (Evans et al., 1989). Given the extraordinary toll AD takes on patients and their families, the rapidly growing number of people in older age groups (Hebert et al., 2001), and the financial burden that it is projected to take on communities around the world by the time today's young adults become senior citizens (Brookmeyer et al., 1998), there is an urgent need to find demonstrably effective treatments for this disease. One of the major challenges to the development of AD treatments is finding the means to evaluate them in the most cost-effective, rapid and rigorous way (Reiman and Langbaum, 2009).
Due to the slow progression of cognitive decline and test–retest variability in the clinical endpoints used in randomized clinical trials (RCTs), it currently takes too many subjects, too much time and too much money to evaluate AD-slowing treatments, especially in the earliest symptomatic and pre-symptomatic stages of AD. For these and other reasons, researchers have sought to develop biomarker endpoints that reflect AD progression or pathology and that could help to assess putative AD-slowing treatments with better statistical power than clinical endpoints (Jones et al., 2009, Landau et al., 2009). To date, the best established biomarkers of AD progression are volumetric magnetic resonance imaging (MRI) measurements of brain shrinkage (Fox et al., 1999, Fox et al., 2000, Hua et al., 2009, Jack et al., 2008, Schuff et al., 2009) and fluorodeoxyglucose positron emission tomography (FDG PET) measurements of regional cerebral metabolic rate for glucose (CMRgl) decline (Alexander et al., 2002, Reiman and Langbaum, 2009, Reiman et al., 2001) and the best established biomarkers of AD pathology are fibrillar amyloid-β (Aβ) PET measurements using Pittsburgh Compound B (PiB) and other recently developed radioligands (Doraiswamy et al., 2009, Jack et al., 2009, Johnson et al., 2009, Klunk et al., 2004, Nyberg et al., 2009, Shoghi-Jadid et al., 2002, Small et al., 2006) and cerebrospinal fluid (CSF) Aβ, total tau and phospho-tau levels (Fagan et al., 2006, Fagan et al., 2007, Fagan et al., 2009, Hansson et al., 2006, Hansson et al., 2009, Li et al., 2007, Sunderland et al., 2004).
FDG PET studies find characteristic and progressive CMRgl reductions in posterior cingulate, precuneus, parietal, temporal and frontal regions in patients with AD and mild cognitive impairment (MCI) (Alexander et al., 2002, de Leon et al., 1983, Drzezga et al., 2003, Foster et al., 1983, Haxby et al., 1990, Herholz et al., 2002, Jagust et al., 1988, Langbaum et al., 2009, Minoshima et al., 1994, Mosconi et al., 2005, Mosconi et al., 2009) and in cognitively normal people at increased genetic risk for AD (Bookheimer et al., 2000, Reiman et al., 1996, Reiman et al., 2001, Reiman et al., 2004, Reiman et al., 2005, Small et al., 1995). A smaller number of studies have also found progressive CMRgl declines in medial temporal and occipital regions in these patients (Alexander et al., 2002, Mielke et al., 1994). We and our colleagues previously used FDG PET and statistical parametric mapping (SPM) to characterize twelve-month regional CMRgl declines in probable AD patients, and we estimated the number of patients per group needed to detect treatment effects in a twelve-month single-center RCT using the atlas coordinates associated with maximal CMRgl declines (two-tailed p < 0.01, uncorrected for multiple comparisons) (Alexander et al., 2002). The number of patients needed to detect significant treatment effects was about one-tenth of that needed using the Mini-Mental State Examination (MMSE) (Folstein et al., 1975), a measure of clinical progression, and roughly comparable to that reported in an earlier study using volumetric MRI measurements of whole-brain atrophy (Fox et al., 2000). In another study, we characterized 24-month regional CMRgl declines in cognitively normal, late-middle-aged carriers of the APOE ε4 allele, the major AD susceptibility gene and estimated the need for relatively fewer than 200 subjects per group to help test putative pre-symptomatic treatments in a 24-month RCT, thus suggesting the feasibility of using these biomarker endpoints to conduct prevention studies in a cost-effective way (Reiman et al., 2001).
Launched in 2004 by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, the Foundation for the National Institutes of Health, private pharmaceutical companies, and nonprofit organizations, the AD Neuroimaging Initiative (ADNI) is an ongoing, multi-center, longitudinal study intended to assist in the early detection and tracking of AD and the design of multi-center clinical trials using brain-imaging and other endpoints. ADNI capitalizing on standardized data acquisition methods makes publicly available clinical, cognitive, volumetric MRI, FDG PET, Pittsburgh Compound B (PiB) PET, cerebral spinal fluid (CSF) and genetic data, and biological fluid samples in probable AD patients, MCI patients, and normal control (NC) subjects (http://www.loni.ucla.edu/ADNI/About/About_Funding.shtml). It is primarily intended to characterize and compare different measures of AD progression and pathology in the detection and tracking of AD, characterize the extent to which the biomarker measurements are correlated with measurements of cognitive and clinical decline, and compare these different measurements—including those using different imaging modalities and image-analysis techniques—in the estimated number of AD and MCI patients per group needed to detect effects of AD-slowing treatments in multi-center RCTs (Hua et al., 2009, Mueller et al., 2005a, Mueller et al., 2005b, Shaw et al., 2007).
As members of ADNI's PET Coordinating Center, we are responsible for conducting voxel-based analyses of FDG PET images using SPM. In this report, we characterize and compare twelve-month CMRgl declines in the probable AD patients, MCI patients, and NC subjects. We introduce the use of an empirically pre-defined spatially distributed statistical region-of-interest (sROI), comprised of the set of voxels consistently associated with longitudinal change, to optimize the power to characterize these declines and evaluate AD-slowing treatments in RCTs. This provides a single imaging endpoint that could be used in RCTs, free from issues associated with multiple comparisons. The sROI can also be customized to particular subject samples and study durations using voxel-based image-analysis techniques. sROIs were empirically pre-defined in AD and MCI patient training sets using SPM, and were then applied to independent AD and MCI patient test sets to demonstrate the reproducibility of these declines and their correlation with measures of cognitive decline, and estimate the number of patients needed per group to detect AD-slowing treatment effects in twelve-month multi-center RCTs. (For more information about ADNI, including the procedures and time-points not included in this report, please see http://adni-info.org/images/stories/adniproceduresmanual12.pdf).
Section snippets
Subjects
At the time of the analyses reported here, an ADNI database search indentified 69 mild AD patients, 154 amnestic MCI patients and 79 NCs from about 50 clinical sites who had undergone baseline and twelve-month follow-up FDG PET scans available for downloading from the ADNI Laboratory of Neuroimaging website (www.loni.ucla.edu/ADNI/). The AD patients met NINCDS-ADRDA criteria for probable AD (McKhann et al., 1984), had MMSE scores between 20 and 26, and had Clinical Diagnostic Rating scores
Subject characteristics
Each subject group's demographic characteristics, proportion of subjects with 0, 1, or 2 copies of the APOE ε4 allele, baseline clinical ratings, twelve-month clinical declines, and mean (SD) interval between the baseline and approximately twelve-month follow-up scans are shown in Table 1. With the exception of a slightly lower mean educational level in the probable AD group (p = 0.01), the probable AD, MCI and NC groups did not differ significantly in their mean age, or sex distribution. As
Discussion
In this study, we used FDG PET images from ADNI to demonstrate twelve-month CMRgl declines in probable AD and MCI. Using SPM5 to analyze FDG PET data from this unusually large multi-center study, mild probable AD patients and amnestic MCI patients each had twelve-month regional-to-whole-brain CMRgl declines bilaterally in posterior cingulate, medial and lateral parietal, medial and lateral temporal, and occipital regions. We also used these data to introduce the use of an empirically
Acknowledgments
The authors thank Justin Venditti and Amrapali Arshanapalli for their support and technical assistance.
Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI; Principal Investigator: Michael Weiner; NIH grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering (NIBIB), and through generous contributions from the following: Pfizer Inc., Wyeth Research,
References (61)
- et al.
Relationship between regional amyloid levels and cognitive performance in healthy controls, MCI subjects, and patients with AD: phase II results from a florpiramine F18 PET imaging study
Alzheimer's Dement.
(2009) - et al.
“Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician
J. Psychiatr. Res.
(1975) - et al.
Serial magnetic resonance imaging of cerebral atrophy in preclinical Alzheimer's disease
Lancet
(1999) - et al.
Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study
Lancet Neurol.
(2006) - et al.
Combined rCBF and CSF biomarkers predict progression from mild cognitive impairment to Alzheimer's disease
Neurobiol. Aging
(2009) - et al.
Discrimination between Alzheimer dementia and controls by automated analysis of multicenter FDG PET
Neuroimage
(2002) - et al.
Optimizing power to track brain degeneration in Alzheimer's disease and mild cognitive impairment with tensor-based morphometry: an ADNI study of 515 subjects
Neuroimage
(2009) - et al.
Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer's Disease Neuroimaging Initiative (ADNI)
Neuroimage
(2009) - et al.
Posterior cingulate cortex in Alzheimer's disease
Lancet
(1994) - et al.
Ways toward an early diagnosis in Alzheimer's disease: the Alzheimer's Disease Neuroimaging Initiative (ADNI)
Alzheimers Dement.
(2005)
The Alzheimer's disease neuroimaging initiative
Neuroimaging Clin. N. Am.
Twelve-month cerebral metabolic declines in probable Alzheimer's disease and amnestic mild cognitive impairment: preliminary findings from the Alzheimer's disease neuroimaging initiative (ADNI)
Alzheimers Dement.
Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease
Am. J. Geriatr. Psychiatry
Cerebrospinal fluid beta-amyloid1-42 and tau in control subjects at risk for Alzheimer's disease: the effect of APOE epsilon4 allele
Biol. Psychiatry
Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain
Neuroimage
Longitudinal PET evaluation of cerebral metabolic decline in dementia: a potential outcome measure in Alzheimer's disease treatment studies
Am. J. Psychiatry
Patterns of brain activation in people at risk for Alzheimer's disease
N. Engl. J. Med.
Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset
Am. J. Public Health
Computed tomography and positron emission transaxial tomography evaluations of normal aging and Alzheimer's disease
J. Cereb. Blood Flow Metab.
Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer's disease: a PET follow-up study
Eur. J. Nucl. Med. Mol. Imaging
Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported
JAMA
Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Ab42 in humans
Ann. Neurol.
Cerebrospinal fluid tau/b-amyloid42 ratio as a prediction of cognitive decline in nondemented older adults
Arch. Neurol.
Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly
Ann. Neurol.
Alzheimer's disease: focal cortical changes shown by positron emission tomography
Neurology
Using serial registered brain magnetic resonance imaging to measure disease progression in Alzheimer disease: power calculations and estimates of sample size to detect treatment effects
Arch. Neurol.
Longitudinal study of cerebral metabolic asymmetries and associated neuropsychological patterns in early dementia of the Alzheimer type
Arch. Neurol.
Annual incidence of Alzheimer disease in the United States projected to the years 2000 through 2050
Alzheimer Dis. Assoc. Disord.
Comparing 3 T and 1.5 T MRI for tracking Alzheimer's disease progression with tensor-based morphometry
Human Brain Mapping.
11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment
Brain
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Data used in this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). ADNI investigators other than those listed above contributed to study design, implementation or data provision but did not participate in the analyses or writing of this report. The complete listing of ADNI investigators is available at http://www.loni.ucla.edu/ADNI/Data/ADNI_Authorship_List.pdf.